Pyridine and pyrazine derivative for the treatment of CF

ABSTRACT

The present invention provides pyridine and pyrazine derivatives which restore or enhance the function of mutant and/or wild type CFTR to treat cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory tract infections, lung carcinoma, xerostomia and keratoconjunctivitis sire, or constipation (IBS, IBD, opioid induced). Pharmaceutical compositions comprising such derivatives are also encompassed.

This application is a Continuation of U.S. application Ser. No.13/047,319, filed on Mar. 14, 2011, which claims benefit under 35 U.S.C.§119(e) of US Provisional Application No. 61/315,509, filed Mar. 19,2010, and U.S. Provisional Application No. 61/441,853, filed on Feb. 11,2011, the contents of which are incorporated herein by reference intheir entirety.

This invention relates to pyridine and pyrazine compounds, theirpreparation and use as pharmaceuticals.

Cystic fibrosis (CF) is a fatal genetic disease caused by mutations inthe gene encoding the CF transmembrane conductance regulator (CFTR), aprotein kinase A (PKA)-activated epithelial anion channel involved insalt and fluid transport in multiple organs, including the lung. Most CFmutations either reduce the number of CFTR channels at the cell surface(e.g., synthesis or processing mutations) or impair channel function(e.g., gating or conductance mutations) or both. There are currently noapproved therapies that target CFTR directly. The present inventiondiscloses compounds which restore or enhance the function of mutantand/or wild type CFTR to treat cystic fibrosis, primary ciliarydyskinesia, chronic bronchitis, chronic obstructive pulmonary disease,asthma, respiratory tract infections, lung carcinoma, xerostomia andkeratoconjunctivitis sire, or constipation (IBS, IBD, opioid induced).

In one aspect, the invention provides compounds according to Formula I:

or pharmaceutically acceptable salts thereof, wherein:A is N or CR^(4a);R¹ is H; C₁-C₈ alkyl optionally substituted by one or more halogenatoms; C₂-C₉ alkenyl; C₂-C₈ alkynyl; C₃-C₁₀ cycloalkyl; C₅-C₁₀cycloalkenyl; —C₁-C₄ alkyl-C₃-C₈ cycloalkyl; C₁-C₈ alkoxy optionallysubstituted by one or more halogen atoms; halogen; SO₂NR⁸R⁹; SO₂R¹⁹;S—C₁-C₈alkyl optionally substituted by one or more halogen atoms;S—C₆-C₁₄ aryl; CN; NR¹¹R¹²; C(O)NR¹³R¹⁴; NR¹³SO₂R¹⁵; NR¹³C(O)R¹⁵,CO₂R¹⁵, —(C₀-C₄ alkyl)-C₈-C₁₋₄ aryl; or —(C₀-C₄ alkyl)-3 to 14 memberedheterocyclic group, wherein the heterocyclic group contains at least oneheteroatom selected from N, O and S; wherein the cycloalkyl,cycloalkenyl, aryl and heterocyclyl groups are each optionallysubstituted by one or more Z substituents;R² is C₁-C₄ haloalkyl;R³ and R^(4a) are each independently H or C₁-C₈ alkyl optionallysubstituted by one or more halogen atoms;R⁴ is H, or C₁-C₈ alkyl optional substituted with one or more halogen;R⁵ is —(CH₂), —NR¹⁷R¹⁸, —(CH₂)_(m)—OR′; C₁-C₈ alkoxy optionallysubstituted by one or more halogen atoms; —(C₀-C₄ alkyl)-CO₂R¹⁵; —(C₀-C₄alkyl)-C₆-C₁₄ aryl or -3 to 14 membered heterocyclic group, wherein theheterocyclic group contains at least one heteroatom selected from N, Oand S; wherein the —(C₀-C₄ alkyl)-C₆-C₁₄ aryl and —(C₀-C₄ alkyl)-3 to 14membered heterocyclic group are each optionally substituted by one ormore Z substituents;R⁶ is C₁-C₈ alkyl optionally substituted by one or more halogen atoms;C₃-C₁₀ cycloalkyl; —C₁-C₄ alkyl-C₃-C₈ cycloalkyl; C₁-C₈ alkoxyoptionally substituted by one or more halogen atoms; OH; CN; halogen;—(C₀-C₄ alkyl)-C₆-C₁₄ aryl; or —(C₀-C₄ alkyl)-3 to 14 memberedheterocyclic group, wherein the heterocyclic group contains at least oneheteroatom selected from N, O and S; wherein the cycloalkyl,cycloalkenyl, —(C₀-C₄ alkyl)-C₆-C₁₄ aryl and —(C₀-C₄ alkyl)-3 to 14membered heterocyclic group are each optionally substituted by one ormore Z substituents; orR⁶ is H, and R⁵ is —(CH₂)_(m)—NR¹⁷R¹⁸, —(CH₂)_(m)—OR′, C₁-C₈ alkoxyoptionally substituted by one or more halogen atoms; —(C₀-C₄alkyl)-C₆-C₁₄ aryl; —(C₀-C₄ alkyl)-3 to 14 membered heterocyclic group,wherein the heterocyclic group contains at least one heteroatom selectedfrom N, O and S; or —(C₀-C₄ alkyl)-CO₂R¹⁵, wherein —(C₀-C₄ alkyl)-C₆-C₁₄aryl and —(C₀-C₄ alkyl)-3 to 14 membered heterocyclic group groups areeach optionally substituted by one or more Z substituents; orR⁴ and R⁶ together with the carbon atoms to which they are bound form a3 to 8 membered carbocyclic ring system; orR⁴ and R⁵ together form an oxo group (C═O) and R⁶ is C₁-C₄ alkyloptionally substituted by one or more halogen atoms; C₁-C₄ alkoxyoptionally substituted by one or more halogen atoms; —(C₀-C₄alkyl)-C₆-C₁₄ aryl; or —(C₀-C₄ alkyl)-3 to 14 membered heterocyclicgroup, wherein the heterocyclic group contains at least one heteroatomselected from N, O and S, wherein the aryl and heterocyclyl groups areeach optionally substituted by one or more Z substituents; orR⁵ and R⁶ together with the carbon atoms to which they are bound a 5 to8 membered heterocyclic ring system containing one or more heteroatomsselected from N, O and S, wherein the ring system is optionallysubstituted by one or more Z substituents; orR⁴ and R⁵ and R⁶ together with the carbon atoms to which they are boundform a 5 to 8 membered heterocyclic ring system containing one or moreheteroatoms selected from N, O and S, wherein the ring system isoptionally substituted by one or more Z substituents;R′ is H, or C₁-C₈ alkyl optional substituted with one or more halogen;m is 0, 1, 2 or 3;R⁸, R¹¹, R¹³ and R¹⁷ are each independently H, C₁-C₈ alkyl optionallysubstituted by one or more halogen atoms, C₃-C₁₀ cycloalkyl or —(C₁-C₄alkyl)-C₃-C₈ cycloalkyl;R⁹, R¹⁰, R¹², R¹⁴, R¹⁵, R¹⁶ and R¹⁸ are each independently H; C₁-C₈alkyl optionally substituted by one or more halogen atoms; C₂-C₈alkenyl; C₂-C₈ alkynyl; C₃-C₁₀ cycloalkyl; C₅-C₁₀ cycloalkenyl; —C₁-C₄alkyl-C₃-C₈ cycloalkyl; —(C₀-C₄ alkyl)-C₆-C₁₄ aryl; or —(C₀-C₄ alkyl)-3to 14 membered heterocyclic group, wherein the heterocyclic groupcontains at least one heteroatom selected from N, O and S, wherein thecycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are eachoptionally substituted by one or more Z substituents; orR⁸ and R⁹, R¹¹ and R¹², R¹³ and R¹⁴, and R¹⁷ and R¹⁸ together with thenitrogen atom to which they are attached may form a 4 to 14 memberedheterocyclic group optionally substituted by one or more Z substituents;Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C₁-C₆ alkyloptionally substituted by one or more OH groups or NH₂ groups, C₁-C₆alkyl optionally substituted by one or more halogen atoms, C₁-C₆ alkoxyoptionally substituted by one or more OH groups or C₁-C₄ alkoxy,NR¹⁸(SO₂)R²¹, (SO₂)NR¹⁹R²¹, (SO₂)R²¹, NR¹⁸C(O)R²¹, C(O)NR¹⁹R²¹,NR¹⁸C(O)NR¹⁹R²¹, NR¹⁸C(O)OR¹⁹, NR¹⁹R²¹, C(O)OR¹⁹, C(O)R¹⁹, SR¹⁹, OR¹⁹,oxo, CN, NO₂, halogen or a 3 to 14 membered heterocyclic group, whereinthe heterocyclic group contains at least one heteroatom selected from N,O and S;R¹⁹ and R²¹ are each independently H; C₁-C₈ alkyl; C₃-C₈ cycloalkyl;C₁-C₄ alkoxy-C₁-C₄ alkyl; (C₀-C₄ alkyl)-aryl optionally substituted byone or more groups selected from C₁-C₆ alkyl, C₁-C₆ alkoxy and halogen;(C₀-C₄ alkyl)-3- to 14-membered heterocyclic group, the heterocyclicgroup including one or more heteroatoms selected from N, O and S,optionally substituted by one or more groups selected from halogen, oxo,C₁-C₆ alkyl and C(O)C₁-C₆ alkyl; (C₀-C₄ alkyl)-O-aryl optionallysubstituted by one or more groups selected from C₁-C₆ alkyl, C₁-C₆alkoxy and halogen; and (C₀-C₄ alkyl)-O-3- to 14-membered heterocyclicgroup, the heterocyclic group including one or more heteroatoms selectedfrom N, O and S, optionally substituted by one or more groups selectedfrom halogen, C₁-C₆ alkyl or C(O)C₁-C₆ alkyl; wherein the alkyl groupsare optionally substituted by one or more halogen atoms, C₁-C₄ alkoxy,C(O)NH₂, C(O)NHC₁-C₆ alkyl or C(O)N(C₁-C₆ alkyl)₂; orR¹⁹ and R²¹ together with the nitrogen atom to which they attached forma 5- to 10-membered heterocyclic group, the heterocyclic group includingone or more further heteroatoms selected from N, O and S, theheterocyclic group being optionally substituted by one or moresubstituents selected from OH; halogen; aryl; 5- to 10-memberedheterocyclic group including one or more heteroatoms selected from N, Oand S; S(O)₂-aryl; S(O)₂—C₁-C₆ alkyl; C₁-C₆ alkyl optionally substitutedby one or more halogen atoms; C₁-C₆ alkoxy optionally substituted by oneor more OH groups or C₁-C₄ alkoxy; and C(O)OC₁-C₆ alkyl, wherein thearyl and heterocyclic substituent groups are themselves optionallysubstituted by C₁-C₆ alkyl, C₁-C₆ haloalkyl or C₁-C₆ alkoxy.

Various embodiments of the invention are described herein. It will berecognized that features specified in each embodiment may be combinedwith other specified features to provide further embodiments.

In an embodiment of the invention as described anywhere herein, A is N.

In an embodiment of the invention as described anywhere herein, A isCR^(4a).

In an embodiment of the invention as described anywhere herein, R¹ isselected from H; C₁-C₈ alkyl optionally substituted by one or morehalogen atoms; C₁-C₈ alkoxy optionally substituted by one or morehalogen atoms; halogen; C₆-C₁₄ aryl; —(C₀-C₄ alkyl)-3 to 14 memberedheterocyclic group, wherein the heterocyclic group contains at least oneheteroatom selected from N, O and S; and NR¹¹R¹², wherein the aryl andheterocyclic groups are each optionally substituted by one or more Zsubstituents.

In an embodiment of the invention as described anywhere herein, R¹ isC₁-C₄ alkyl optional substituted by one or more halogen atoms. Forexample, —CH₃ or CF₃.

In an embodiment of the invention as described anywhere herein, R¹ isC₁-C₄ alkoxy optional substituted by one or more halogen atoms. Forexample, —OCH₃ or —OCF₃.

In an embodiment of the invention as described anywhere herein, R¹ isaryl, wherein aryl is phenyl optionally substituted by one or more Zsubstituents, specific example are 4-fluorophenyl,4-chloro-2-methylphenyl, or 2,4-dichlorophenyl.

In an embodiment of the invention as described anywhere herein, R¹ is 6membered heterocyclyl group, wherein 6 membered heterocyclyl group ispyridyl optionally substituted by one or more Z substituents, specificexample is 1-methyl-4-pyridyl.

In an embodiment of the invention as described anywhere herein, R¹ isBr, —CH₃, —CF₃, —OCH₃, —OCF₃, 4-fluorophenyl, 4-chloro-2-methylphenyl,or 2,4-dichlorophenyl.

In an embodiment of the invention as described anywhere herein, R² isCF₃CF₂—, (CF₃)₂CH—, CH₃—CF₂—, CF₃CF₂—, CF₃, CF₂H—, CH₃—CCl₂—,CF₃CFCClH—, CBr₃, CBr₂H—CF₃CF₂CHCF₃ or CF₃CF₂CF₂CF₂—.

In an embodiment of the invention as described anywhere herein, R² isCF₃.

In an embodiment of the invention as described anywhere herein, R³ is Hor methyl.

In a further embodiment of the invention as described anywhere herein,R^(4a) is H.

An embodiment of the invention, as defined above provides a compound,where R⁵ provides a heteroatom two carbons from the amide nitrogen,wherein the heteroatom is oxygen or nitrogen.

An embodiment of the invention as defined above provides a compoundaccording to Formula I, wherein

-   -   R⁴ is H, C₁-C₄ alkyl optionally substituted by one or more        halogen atoms or not present;    -   R⁵ is C₁-C₄ alkoxy optionally substituted by one or more halogen        atoms; —(CH₂)_(m)—NR¹⁷R¹⁸; —(CH₂)_(m)—OR′, or OH;    -   m is 0, or 1;    -   R⁶ is C₁-C₄ alkyl optionally substituted by one or more halogen        atoms; C₁-C₄ alkoxy optionally substituted by one or more        halogen atoms; OH; CN; halogen; —(C₀-C₄ alkyl)-C₆-C₁₄ aryl; or        —(C₀-C₄ alkyl)-3 to 14 membered heterocyclic group, wherein the        heterocyclic group contains at least one heteroatom selected        from N, O and S, wherein the aryl and heterocyclyl groups are        each optionally substituted by one or more Z substituents; or    -   R⁴ and R⁵ together form an oxo group (C═O); or    -   R⁵ and R⁶ together with the carbon atoms to which they are bound        form a 5 to 8 membered heterocyclic ring system containing one        or more heteroatoms selected from N, O and S, wherein the ring        system is optionally substituted by one or more Z substituents;    -   R¹⁷ and R¹⁸ are each independently H; or C₁-C₄ alkyl optionally        substituted by one or more halogen atoms.

An embodiment of the invention as defined above provides compoundsaccording to Formula I, wherein

-   -   A is CR^(4a);    -   R¹ is halogen, C₁-C₄ alkyl optionally substituted by one or more        halogen atoms, or C₁-C₄ alkoxy optionally substituted by one or        more halogen atoms;    -   R² is C₁-C₄ haloalkyl;    -   R³ is H;    -   R⁴ is H or Me;    -   R^(4a) is H;    -   R⁵ is —(CH₂)_(m)—NR¹⁷R¹⁸; —(CH₂)_(m)—OR′; or OH;    -   m is 0, or 1;    -   R⁶ is C₁-C₄ alkyl optionally substituted by one or more halogen        atoms; or    -   R⁵ and R⁶ together with the carbon atoms to which they are bound        form a 5 to 6 membered heterocyclic ring system containing one        or more heteroatoms selected from N, O and S, wherein the ring        system is optionally substituted by one or more Z substituents;        and    -   R¹⁷ and R¹⁸ are each independently H; or C₁-C₄ alkyl optionally        substituted by one or more halogen atoms.

An embodiment of the invention as defined above provides compoundsaccording to Formula I, wherein

-   -   A is CR^(4a);    -   R¹ is halogen, C₁-C₄ alkyl optionally substituted by one or more        halogen atoms, or C₁-C₄ alkoxy optionally substituted by one or        more halogen atoms;    -   R² is C₁-C₄ haloalkyl;    -   R³ is H;    -   R^(4a) is H;    -   R⁴ and R⁵ together form an oxo group (C═O); and    -   R⁶ is C₁-C₄ alkyl optionally substituted by one or more halogen        atoms; C₁-C₄ alkoxy optionally substituted by one or more        halogen atoms; —(C₀-C₄ alkyl)-C₆-C₁₄ aryl; or —(C₀-C₄ alkyl)-3        to 14 membered heterocyclic group, wherein the heterocyclic        group contains at least one heteroatom selected from N, O and S,        wherein the aryl and heterocyclyl groups are each optionally        substituted by one or more Z substituents.

An embodiment of the invention as defined above provides compoundsaccording to Formula I, wherein

-   -   A is CR^(4a);    -   R¹ is C₁-C₄ alkyl optionally substituted by one or more halogen        atoms;    -   R² is C₁-C₄ haloalkyl;    -   R³ is H;    -   R⁴ is H or Me;    -   R^(4a) is H;    -   R⁵ is —(CH₂)_(m)—NR¹⁷R¹⁸; —(CH₂)_(m)—OR′; or OH;    -   m is 0, or 1;    -   R⁶ is C₁-C₄ alkyl optionally substituted by one or more halogen        atoms; or    -   R⁵ and R⁶ together with the carbon atoms to which they are bound        form a 5 to 6 membered heterocyclic ring system containing one        or more heteroatoms selected from N, O and S, wherein the ring        system is optionally substituted by one or more Z substituents;        and    -   R¹⁷ and R¹⁸ are each independently H; or C₁-C₄ alkyl optionally        substituted by one or more halogen atoms.

An embodiment of the invention as defined above provides compoundsaccording to Formula I, wherein

-   -   A is CR^(4a);    -   R¹ is C₁-C₄ alkoxy optionally substituted by one or more halogen        atoms;    -   R² is C₁-C₄ haloalkyl;    -   R³ is H;    -   R⁴ is H or Me;    -   R^(4a) is H;    -   R⁵ is —(CH₂)_(m)—NR¹⁷R¹⁸; —(CH₂)_(m)—OR; or OH;    -   m is 0, or 1;    -   R⁶ is C₁-C₄ alkyl optionally substituted by one or more halogen        atoms; or    -   R⁵ and R⁶ together with the carbon atoms to which they are bound        form a 5 to 6 membered heterocyclic ring system containing one        or more heteroatoms selected from N, O and S, wherein the ring        system is optionally substituted by one or more Z substituents;        and    -   R¹⁷ and R¹⁸ are each independently H; or C₁-C₄ alkyl optionally        substituted by one or more halogen atoms.

An embodiment of the invention as defined above provides compoundsaccording to Formula I, wherein

-   -   A is CR^(4a);    -   R¹ is C₁-C₄ alkoxy optionally substituted by one or more halogen        atoms;    -   R² is C₁-C₄ haloalkyl;    -   R³ is H;    -   R⁴ is H or Me;    -   R^(4a) is H ;    -   R⁵ is —NR¹⁷R¹⁸; or OH;    -   R⁶ is C₁-C₄ alkyl optionally substituted by one or more halogen        atoms; or    -   R⁵ and R⁶ together with the carbon atoms to which they are bound        form a 5 to 6 membered heterocyclic ring system containing one        or more heteroatoms selected from N, O and S, wherein the ring        system is optionally substituted by one or more Z substituents;        and    -   R¹⁷ and R¹⁸ are each independently H; or C₁-C₄ alkyl optionally        substituted by one or more halogen atoms.

An embodiment of the invention as defined above provides compoundsaccording to Formula I, wherein

-   -   A is CR^(4a);    -   R¹ is C₁-C₄ alkyl optionally substituted by one or more halogen        atoms;    -   R² is C₁-C₄ haloalkyl;    -   R³ is H;    -   R⁴ is H or Me;    -   R^(4a) is H;    -   R⁵ is —NR¹⁷R¹⁸; or OH;    -   R⁶ is C₁-C₄ alkyl optionally substituted by one or more halogen        atoms; and    -   R¹⁷ and R¹⁸ are each independently H; or C₁-C₄ alkyl optionally        substituted by one or more halogen atoms.

An embodiment of the invention as defined above provides compoundsaccording to Formula I, wherein

-   -   A is CR^(4a);    -   R¹ is C₁-C₄ alkoxy optionally substituted by one or more halogen        atoms;    -   R² is C₁-C₄ haloalkyl;    -   R³ is H;    -   R⁴ is H or Me;    -   R^(4a) is H;    -   R⁵ is —NR¹⁷R¹⁸; or OH;    -   R⁶ is C₁-C₄ alkyl optionally substituted by one or more halogen        atoms; and    -   R¹⁷ and R¹⁸ are each independently H; or C₁-C₄ alkyl optionally        substituted by one or more halogen atoms.

In an embodiment of the invention as described anywhere herein, wherein

-   -   Z is independently OH, C₁-C₄ alkyl optionally substituted by one        or more OH groups or NH₂ groups, C₁-C₄ alkyl optionally        substituted by one or more halogen atoms, C₁-C₄ alkoxy        optionally substituted by one or more OH groups or C₁-C₄ alkoxy,        NR¹⁹R²¹, C(O)OR¹⁹, C(O)R¹⁹, SR¹⁹, OR¹⁹, CN, NO₂, or halogen;    -   R¹⁹ and R²¹ are each independently H; C₁-C₄ alkyl; C₃-C₆        cycloalkyl; or C₁-C₄ alkoxy-C₁-C₄ alkyl, wherein all alkyls are        optionally substituted with halogens.

In an embodiment of the invention as described anywhere herein, wherein

-   -   Z is independently OH, C₁-C₄ alkyl optionally substituted by one        or more OH groups or NH₂ groups, C₁-C₄ alkyl optionally        substituted by one or more halogen atoms, C₁-C₄ alkoxy        optionally substituted by one or more OH groups or C₁-C₄ alkoxy,        C(O)OR¹⁹, C(O)R¹⁹, OR¹⁹, CN, or halogen;    -   R¹⁹ is H; C₁-C₄ alkyl; C₃-C₆ cycloalkyl; or C₁-C₄ alkoxy-C₁-C₄        alkyl, wherein all alkyl are optionally substituted with        halogens.

In an embodiment of the invention as described anywhere herein, wherein

-   -   Z is independently, C₁-C₄ alkyl optionally substituted by one or        more halogen atoms, C₁-C₄ alkoxy or halogen.

Another embodiment of the invention as defined above provides compoundswith substantially pure enantiomers with the R configuration.

Another embodiment of the invention as defined above provides compoundswith substantially pure enantiomers with the S configuration.

Certain compounds of Formula I include compounds of Formula II:

or a pharmaceutically acceptable salt thereof, wherein A, R¹, R² and R³have the definitions of Formula I and

R¹⁰¹ is

In a further embodiment of Formula II of the invention herein, A isCR^(4a), wherein R^(4a) is H.

In a further embodiment of Formula II of the invention herein, R¹ isselected from H; C₁-C₄ alkyl optionally substituted by one or morehalogen atoms; C₁-C₄ alkoxy optionally substituted by one or morehalogen atoms; halogen; C₆-C₁₄ aryl; —(C₀-C₄ alkyl)-3 to 14 memberedheterocyclic group, wherein the heterocyclic group contains at least oneheteroatom selected from N, O and S; and NR¹¹R¹², wherein the aryl andheterocyclic groups are each optionally substituted by one or more Zsubstituents.

In a further embodiment of Formula II of the invention wherein, R¹ isC₁-C₄ alkyl optional substituted by one or more halogen atoms, C₁-C₄alkoxy optionally substituted by one or more halogen atoms; halogen; C₆aryl; or 6 membered heterocyclic group, wherein the heterocyclic groupcontains at least one heteroatom selected from N, O and S, wherein thearyl and heterocyclic groups are each optionally substituted by one ormore Z substituents.

In a further embodiment of Formula II of the invention wherein, R¹ isC₁-C₄ alkyl optional substituted by one or more halogen atoms, C₁-C₄alkoxy optionally substituted by one or more halogen atoms; or halogen.

In a further embodiment of Formula II of the invention herein, R³ is Hor methyl.

An embodiment of the invention as defined above provides compoundsaccording to Formula II, wherein

-   -   A is CR^(4a);    -   R¹ is halogen;    -   R³ is H;    -   R^(4a) is H;    -   R¹⁰¹ is

An embodiment of the invention as defined above provides compoundsaccording to Formula II, wherein

-   -   A is CR^(4a);    -   R¹ is C₁-C₄ alkyl optionally substituted by one or more halogen        atoms;    -   R³ is H;    -   R^(4a) is H;    -   R¹⁰¹ is

An embodiment of the invention as defined above provides compoundsaccording to Formula II, wherein

-   -   A is CR^(4a);    -   R¹ is C₁-C₄ alkoxy optionally substituted by one or more halogen        atoms;    -   R³ is H;    -   R^(4a) is H;    -   R¹⁰¹ is

An embodiment of the invention as defined above provides compoundsaccording to Formula II, wherein

-   -   A is CR^(4a);    -   R¹ is halogen, C₁-C₄ alkyl optionally substituted by one or more        halogen atoms, or C₁-C₄ alkoxy optionally substituted by one or        more halogen atoms;    -   R³ is H;    -   R^(4a) is H;    -   R¹⁰¹ is

An embodiment of the invention as defined above provides compoundsaccording to Formula II, wherein

-   -   A is CR^(4a);    -   R¹ is halogen, C₁-C₄ alkyl optionally substituted by one or more        halogen atoms, or C₁-C₄ alkoxy optionally substituted by one or        more halogen atoms;    -   R³ is H;    -   R^(4a) is H;    -   R¹⁰¹ is

An embodiment of the invention as defined above provides compoundsaccording to Formula II, wherein

-   -   A is CR^(4a);    -   R¹ is halogen, C₁-C₄ alkyl optionally substituted by one or more        halogen atoms, or C₁-C₄ alkoxy optionally substituted by one or        more halogen atoms;    -   R³ is H;    -   R^(4a) is H;    -   R¹⁰¹ is

Another embodiment of the invention as defined above provides compoundsaccording to Formula I and Formula II, represented by

-   3-amino-6-bromo-N-(imidazo[1,2-a]pyridin-2-ylmethyl)-5-(trifluoromethyl)pyrazine-2-carboxamide;-   3-amino-6-bromo-N-((1-methyl-1H-imidazol-4-yl)methyl)-5-(trifluoromethyl)pyrazine-2-carboxamide;-   3-amino-6-bromo-N-((1-methyl-1H-pyrazol-3-yl)methyl)-5-(trifluoromethyl)pyrazine-2-carboxamide;-   3-amino-N-(2-(4-fluorophenyl)-2-oxoethyl)-6-(1-methyl-1H-indol-6-yl)-5-(trifluoromethyl)picolinamide;-   3-amino-6-bromo-N-((1-methyl-1H-imidazol-2-yl)methyl)-5-(trifluoromethyl)pyrazine-2-carboxamide;-   3-amino-6-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-N-(2-(4-fluorophenyl)-2-oxoethyl)-5-(trifluoromethyl)pyrazine-2-carboxamide;-   (R)-3-amino-6-bromo-N-((4-methylpiperazin-2-yl)methyl)-5-(trifluoromethyl)pyrazine-2-carboxamide;-   3-amino-6-bromo-N-((1-methyl-1H-imidazol-5-yl)methyl)-5-(trifluoromethyl)pyrazine-2-carboxamide;-   3-amino-6-(3-(N,N-dimethylsulfamoyl)phenyl)-N-(2-(4-fluorophenyl)-2-oxoethyl)-5-(trifluoromethyl)picolinamide;-   3-amino-6-bromo-N-isobutyl-N-methyl-5-(trifluoromethyl)pyrazine-2-carboxamide;-   3-amino-6-bromo-N-((1-methyl-1H-pyrazol-5-yl)methyl)-5-(trifluoromethyl)pyrazine-2-carboxamide;-   (3-amino-6-bromo-5-(trifluoromethyl)pyrazin-2-yl)(4-methylpiperazin-1-yl)methanone;-   3-amino-6-bromo-N-(2-(pyridin-4-yl)ethyl)-5-(trifluoromethyl)pyrazine-2-carboxamide;-   3-amino-N-(2-(4-fluorophenyl)-2-oxoethyl)-6-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-(trifluoromethyl)picolinamide;-   3-amino-6-(4-carbamoyl-2-methylphenyl)-N-(2-(4-fluorophenyl)-2-oxoethyl)-5-(trifluoromethyl)picolinamide;-   3-amino-6-bromo-N-(2-(pyridin-3-yl)ethyl)-5-(trifluoromethyl)pyrazine-2-carboxamide;-   3-amino-6-(3,4-dimethylphenyl)-N-(2-(4-fluorophenyl)-2-oxoethyl)-5-(trifluoromethyl)picolinamide;-   3-amino-N-benzyl-6-bromo-N-methyl-5-(trifluoromethyl)pyrazine-2-carboxamide;-   (S)-3-amino-6-bromo-N-((1-ethylpyrrolidin-2-yl)methyl)-5-(trifluoromethyl)pyrazine-2-carboxamide;    or-   3-amino-6-bromo-N-(imidazo[1,5-a]pyridin-1-ylmethyl)-5-(trifluoromethyl)pyrazine-2-carboxamide.

Another embodiment of the invention as defined above provides compoundsaccording to Formula I, represented by

-   3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid    ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;-   3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid    ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;-   Methyl    3-(3-amino-6-bromo-5-(trifluoromethyl)picolinamido)propanoate;-   3-Amino-N-(benzo[d]isoxazol-3-ylmethyl)-6-bromo-5-(trifluoromethyl)    picolinamide;-   3-Amino-6-(oxazol-2-yl)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide;-   3-Amino-6-bromo-N-(3,3,3-trifluoro-2-methoxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide;-   3-amino-N-(2-hydroxy-3-methyl-2-(trifluoromethyl)butyl)-6-methoxy-5-(trifluoromethyl)picolinamide;-   3-Amino-6-cyclopropyl-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide;-   3-Amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propyl)-5-(trifluoro    methyl)picolinamide;-   5-amino-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-3-(trifluoromethyl)-2,4′-bipyridine-6-carboxamide;-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    (3-methyl-2-oxo-butyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid    [2-(4-fluoro-phenyl)-2-oxo-ethyl]-amide;-   3-Amino-6-furan-2-yl-5-trifluoromethyl-pyrazine-2-carboxylic acid    [2-(2-methoxy-phenyl)-ethyl]-amide;-   3-Amino-6-(1-methyl-1H-pyrazol-4-yl)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide;-   3-amino-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5,6-bis(trifluoromethyl)pyrazine-2-carboxamide;-   N-(2-(1H-imidazol-2-yl)propyl)-3-amino-6-bromo-5-(trifluoromethyl)pyrazine-2-carboxamide;-   3-Amino-6-bromo-N-(2-morpholinoethyl)-5-(trifluoromethyl)pyrazine-2-carboxamide;-   (S)-3-amino-6-ethoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoro    methyl)picolinamide;-   3-Amino-6-(pyrrolidin-1-yl)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide;-   3-Amino-N-(2-amino-3,3,3-trifluoro-2-methylpropyl)-6-methoxy-5-(trifluoromethyl)    picolinamide; or-   3-Amino-6-methoxy-N-(3,3,3-trifluoro-2-(4-methoxybenzylamino)-2-methylpropyl)-5-(trifluoromethyl)picolinamide.

It is understood that any and all embodiments of the present inventionmay be taken in conjunction with any other embodiment to describeadditional embodiments of the present invention. Furthermore, anyelements of an embodiment are meant to be combined with any and allother elements from any of the embodiments to describe additionalembodiments. It is understood by those skilled in the art thatcombinations of substituents where not possible are not an aspect of thepresent invention.

Especially preferred specific compounds of formula (I) or formula (II)are those described hereinafter in the Examples.

DEFINITIONS

Terms used in the specification have the following meanings:

-   -   “Optionally substituted” means the group referred to can be        substituted at one or more positions by any one or any        combination of the radicals listed thereafter.    -   “Optionally substituted by one or more Z groups” denotes that        the relevant group may include one or more substituents, each        independently selected from the groups included within the        definition of Z. Thus, where there are two or more Z group        substituents, these may be the same or different.    -   “Halo” or “halogen”, as used herein, may be fluorine, chlorine,        bromine or iodine.    -   “C₁-C₈-Alkyl”, as used herein, denotes straight chain or        branched alkyl having 1-8 carbon atoms. If a different number of        carbon atoms is specified, such as C₆ or C₃, then the definition        is to be amended accordingly, such as “C₁-C₄-Alkyl” will        represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl,        sec-butyl and tert-butyl.    -   “C₁-C₈-Alkoxy”, as used herein, denotes straight chain or        branched alkoxy having 1-8 carbon atoms. If a different number        of carbon atoms is specified, such as C₆ or C₃, then the        definition is to be amended accordingly, such as “C₁-C₄-Alkoxy”        will represent methoxy, ethoxy, propoxy, isopropoxy, butoxy,        isobutoxy, sec-butoxy and tert-butoxy.    -   “C₁-C₄-Haloalkyl”, as used herein, denotes straight chain or        branched alkyl having 1-4 carbon atoms with at least one        hydrogen substituted with a halogen. If a different number of        carbon atoms is specified, such as C₆ or C₃, then the definition        is to be amended accordingly, such as “C₁-C₄-Haloalkyl” will        represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl,        sec-butyl and tert-butyl that have at least one hydrogen        substituted with halogen, such as where the halogen is fluorine:        CF₃CF₂—, (CF₃)₂CH—, CH₃—CF₂—, CF₃CF₂—, CF₃, CF₂H—, CF₃CF₂CHCF₃        or CF₃CF₂CF₂CF₂—.    -   “C₃-C₁₅-Cycloalkyl group”, as used herein, denotes a cycloalkyl        group having 3-to 15-ring carbon atoms that is saturated or        partially saturated, such as a C₃-C₈-cycloalkyl. Examples of        C₃-C₁₅-cycloalkyl groups include but are not limited to        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or        cyclooctyl or a bicyclic group, such as bicyclooctyl,        bicyclononyl including indanyl and indenyl and bicyclodecyl. If        a different number of carbon atoms is specified, such as C₆,        then the definition is to be amended accordingly.    -   “aryl” or “C₆-C₁₅-Aromatic carbocyclic group”, as used herein,        denotes an aromatic group having 6- to 15-ring carbon atoms.        Examples of C₆-C₁₅-aromatic carbocyclic groups include, but are        not limited to, phenyl, phenylene, benzenetriyl, naphthyl,        naphthylene, naphthalenetriyl or anthrylene. If a different        number of carbon atoms is specified, such as C₁₀, then the        definition is to be amended accordingly.    -   “4- to 8-Membered heterocyclic group”, “5- to 6-membered        heterocyclic group”, “3- to 10-membered heterocyclic group”, “3-        to 14-membered heterocyclic group”, “4- to 14-membered        heterocyclic group” and “5- to 14-membered heterocyclic group”,        refers, respectively, to 4- to 8-membered, 5- to 6-membered, 3-        to 10-membered, 3- to 14-membered, 4- to 14-membered and 5- to        14-membered heterocyclic rings containing at least one ring        heteroatom selected from the group consisting of nitrogen,        oxygen and sulphur, which may be saturated, partially saturated        or unsaturated (aromatic). The heterocyclic group includes        single ring groups, fused ring groups and bridged groups.        Examples of such heterocyclic groups include, but are not        limited to, furan, pyrrole, pyrrolidine, pyrazole, imidazole,        triazole, isotriazole, tetrazole, thiadiazole, isothiazole,        oxadiazole, pyridine, piperidine, pyrazine, oxazole, isoxazole,        pyrazine, pyridazine, pyrimidine, piperazine, pyrrolidine,        pyrrolidinone, morpholine, triazine, oxazine, tetrahydrofuran,        tetrahydrothiophene, tetrahydrothiopyran, tetrahydropyran,        1,4-dioxane, 1,4-oxathiane, indazole, quinoline, indazole,        indole, 8-aza-bicyclo[3.2.1]octane or thiazole.

A second aspect of the invention provides a compound of Formula (I),(II) or (III) as defined anywhere herein for use as a pharmaceutical.

A further aspect of the invention provides a compound of Formula (I),(II) or (III) for use in the treatment of an inflammatory or allergiccondition, particularly an inflammatory or obstructive airways diseaseor mucosal hydration. Such conditions include, for example, cysticfibrosis, primary ciliary dyskinesia, chronic bronchitis, chronicobstructive pulmonary disease, asthma, respiratory tract infections,lung carcinoma, xerostomia and keratoconjunctivitis sire, orconstipation (IBS, IBD, opioid induced).

A still further aspect of the present invention provides for the use ofa compound of formula (I), (II) or (III), as defined in any of theaforementioned embodiments, in free or pharmaceutically acceptable saltform, for the manufacture of a medicament for the treatment of aninflammatory or allergic condition, particularly an inflammatory orobstructive airways disease or mucosal hydration.

An embodiment of the present invention provides for the use of acompound of formula (I), (II) or (III), as defined in any of theaforementioned embodiments, in free or pharmaceutically acceptable saltform, for the manufacture of a medicament for the treatment of aninflammatory or allergic condition selected from cystic fibrosis,primary ciliary dyskinesia, chronic bronchitis, chronic obstructivepulmonary disease, asthma, respiratory tract infections, lung carcinoma,xerostomia and keratoconjunctivitis sire, or constipation (IBS, IBD,opioid induced).

An embodiment of the present invention provides method for theprevention or treatment of a CFTR mediated condition or diseasecomprising administering an effective amount of at least one compound asdescribed herein to a subject in need of such treatment. Such CFTRmediated condition or disease are selected from cystic fibrosis, primaryciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonarydisease, asthma, respiratory tract infections, lung carcinoma,xerostomia and keratoconjunctivitis sire, or constipation (IBS, IBD,opioid induced).

Throughout this specification and in the claims that follow, unless thecontext requires otherwise, the word “comprise”, or variations such as“comprises” or “comprising”, should be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integers or steps.

As used herein, the term “pharmaceutically acceptable salts” refers tosalts that retain the biological effectiveness and properties of thecompounds of this invention and, which typically are not biologically orotherwise undesirable. In many cases, the compounds of the presentinvention are capable of forming acid and/or base salts by virtue of thepresence of amino and/or carboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulformate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate andtrifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, and sulfosalicylic acid.

Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases.

Inorganic bases from which salts can be derived include, for example,ammonium salts and metals from columns I to XII of the periodic table.In certain embodiments, the salts are derived from sodium, potassium,ammonium, calcium, magnesium, iron, silver, zinc, and copper;particularly suitable salts include ammonium, potassium, sodium, calciumand magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a parent compound, a basic or acidic moiety, byconventional chemical methods. Generally, such salts can be prepared byreacting free acid forms of these compounds with a stoichiometric amountof the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate,bicarbonate or the like), or by reacting free base forms of thesecompounds with a stoichiometric amount of the appropriate acid. Suchreactions are typically carried out in water or in an organic solvent,or in a mixture of the two. Generally, use of non-aqueous media likeether, ethyl acetate, ethanol, isopropanol, or acetonitrile isdesirable, where practicable. Lists of additional suitable salts can befound, e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., MackPublishing Company, Easton, Pa., (1985); and in “Handbook ofPharmaceutical Salts: Properties, Selection, and Use” by Stahl andWermuth (Wiley-VCH, Weinheim, Germany, 2002).

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates, or includeother solvents used for their crystallization.

Compounds of the invention, i.e. compounds of formula (I), (II) or (III)that contain groups capable of acting as donors and/or acceptors forhydrogen bonds may be capable of forming co-crystals with suitableco-crystal formers. These co-crystals may be prepared from compounds offormula (I), (II) or (III) by known co-crystal forming procedures. Suchprocedures include grinding, heating, co-subliming, co-melting, orcontacting in solution compounds of formula (I), (II) or (III) with theco-crystal former under crystallization conditions and isolatingco-crystals thereby formed. Suitable co-crystal formers include thosedescribed in WO 2004/078163. Hence the invention further providesco-crystals comprising a compound of formula (I), (II) or (III).

As used herein, the term “isomers” refers to different compounds thathave the same molecular formula but differ in arrangement andconfiguration of the atoms. Also as used herein, the term “an opticalisomer” or “a stereoisomer” refers to any of the various stereo isomericconfigurations which may exist for a given compound of the presentinvention and includes geometric isomers. It is understood that asubstituent may be attached at a chiral center of a carbon atom.Therefore, the invention includes enantiomers, diastereomers orracemates of the compound. “Enantiomers” are a pair of stereoisomersthat are non-superimposable mirror images of each other. A 1:1 mixtureof a pair of enantiomers is a “racemic” mixture. The term is used todesignate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. The absolute stereochemistry is specifiedaccording to the Cahn-Ingold-Prelog R-S system. When a compound is apure enantiomer the stereochemistry at each chiral carbon may bespecified by either R or S. Resolved compounds whose absoluteconfiguration is unknown can be designated (+) or (−) depending on thedirection (dextro- or levorotatory) which they rotate plane polarizedlight at the wavelength of the sodium D line. Certain of the compoundsdescribed herein contain one or more asymmetric centers or axes and maythus give rise to enantiomers, diastereomers, and other stereoisomericforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)-. The present invention is meant to include all such possibleisomers, including racemic mixtures, optically pure forms andintermediate mixtures. Optically active (R)- and (S)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. If the compound contains a double bond, thesubstituent may be E or Z configuration. If the compound contains adisubstituted cycloalkyl, the cycloalkyl substituent may have a cis- ortrans-configuration. All tautomeric forms are also intended to beincluded.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of thepresent invention can be present in racemic or enantiomericallyenriched, for example the (R)-, (S)- or (R,S)-configuration. In certainembodiments, each asymmetric atom has at least 50% enantiomeric excess,at least 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95% enantiomeric excess, or at least 99% enantiomeric excess inthe (R)- or (S)-configuration. Substituents at atoms with unsaturatedbonds may, if possible, be present in cis- (Z)- or trans- (E)-form.

Accordingly, as used herein a compound of the present invention can bein the form of one of the possible isomers, rotamers, atropisomers,tautomers or mixtures thereof, for example, as substantially puregeometric (cis or trans) isomers, diastereomers, optical isomers(antipodes), racemates or mixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compounds of the present invention into theiroptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O′ p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic products can alsobe resolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

Since the compounds of the invention are intended for use inpharmaceutical compositions it will readily be understood that they areeach preferably provided in substantially pure form, for example atleast 60% pure, more suitably at least 75% pure and preferably at least85%, especially at least 98% pure (% are on a weight for weight basis).Impure preparations of the compounds may be used for preparing the morepure forms used in the pharmaceutical compositions; these less purepreparations of the compounds should contain at least 1%, more suitablyat least 5% and preferably from 10 to 59% of a compound of theinvention.

Compounds of the present invention are either obtained in the free form,as a salt thereof, or as prodrug derivatives thereof.

When both a basic group and an acid group are present in the samemolecule, the compounds of the present invention may also form internalsalts, e.g., zwitterionic molecules.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²⁵Irespectively. The invention includes various isotopically labeledcompounds as defined herein, for example those into which radioactiveisotopes, such as ³H, ¹³C, and ¹⁴C are present. Such isotopicallylabeled compounds are useful in metabolic studies (with ¹⁴C), reactionkinetic studies (with, for example ²H or ³H), detection or imagingtechniques, such as positron emission tomography (PET) or single-photonemission computed tomography (SPECT) including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or labeled compound may be particularly desirable forPET or SPECT studies. Isotopically labeled compounds of this inventioncan generally be prepared by carrying out the procedures disclosed inthe schemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent.

Further, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound of the formula (I), (II) or (III). Theconcentration of such a heavier isotope, specifically deuterium, may bedefined by the isotopic enrichment factor. The term “isotopic enrichmentfactor” as used herein means the ratio between the isotopic abundanceand the natural abundance of a specified isotope. If a substituent in acompound of this invention is denoted deuterium, such compound has anisotopic enrichment factor for each designated deuterium atom of atleast 3500 (52.5% deuterium incorporation at each designated deuteriumatom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5%deuterium incorporation), at least 5000 (75% deuterium incorporation),at least 5500 (82.5% deuterium incorporation), at least 6000 (90%deuterium incorporation), at least 6333.3 (95% deuterium incorporation),at least 6466.7 (97% deuterium incorporation), at least 6600 (99%deuterium incorporation), or at least 6633.3 (99.5% deuteriumincorporation).

Isotopically-labeled compounds of formula (I), (II) or (III) cangenerally be prepared by conventional techniques known to those skilledin the art or by processes analogous to those described in theaccompanying Examples and Preparations using an appropriateisotopically-labeled reagents in place of the non-labeled reagentpreviously employed.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Synthesis

Generally, compounds according to Formula I, II or III can besynthesized by the routes described in Scheme 1, 2 and 3 and theExamples.

When A is CH the pyridinyl moiety may be synthesized according to thegeneral scheme 1 shown below.

When A is nitrogen, the pyrazine moiety may be synthesized according tothe general scheme 2 shown below.

The right hand side of the moiety is typically added via an amideformation reaction as shown below in general scheme 3.

HATU (2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate Methanaminium) is a peptide coupling agent. Askilled artisan would understand that other coupling agents coldpossibly work. The halogen group in the above schemes can be replacedwith other groups by choosing the appropriate nucleophile and catalyst.Protection of the Aryl NH2 group may be required and is represented byP. The schemes 4-7 below are some representative examples.

The skilled person will appreciate that the general synthetic routesdetailed above show common reactions to transform the starting materialsas required. The specific reaction conditions are not provided, butthese are well known to those skilled in the art and appropriateconditions considered to be within the skilled person's common generalknowledge.

The starting materials are either commercially available compounds orare known compounds and can be prepared from procedures described in theorganic chemistry art.

Compounds of formula (I), (II) or (III), in free form, may be convertedinto salt form, and vice versa, in a conventional manner understood bythose skilled in the art. The compounds in free or salt form can beobtained in the form of hydrates or solvates containing a solvent usedfor crystallisation. Compounds of formula (I), (II) or (III) can berecovered from reaction mixtures and purified in a conventional manner.Isomers, such as stereoisomers, may be obtained in a conventionalmanner, e.g., by fractional crystallisation or asymmetric synthesis fromcorrespondingly asymmetrically substituted, e.g., optically active,starting materials.

The compounds of formula (I), (II) or (III) can be prepared, e.g., usingthe reactions and techniques described below and in the Examples. Thereactions may be performed in a solvent appropriate to the reagents andmaterials employed and suitable for the transformations being effected.It will be understood by those skilled in the art of organic synthesisthat the functionality present on the molecule should be consistent withthe transformations proposed. This will sometimes require a judgment tomodify the order of the synthetic steps or to select one particularprocess scheme over another in order to obtain a desired compound of theinvention.

The various substituents on the synthetic intermediates and finalproducts shown in the following reaction schemes can be present in theirfully elaborated forms, with suitable protecting groups where requiredas understood by one skilled in the art, or in precursor forms which canlater be elaborated into their final forms by methods familiar to oneskilled in the art. The substituents can also be added at various stagesthroughout the synthetic sequence or after completion of the syntheticsequence. In many cases, commonly used functional group manipulationscan be used to transform one intermediate into another intermediate, orone compound of formula (I), (II) or (III) into another compound offormula (I), (II) or (III). Examples of such manipulations areconversion of an ester or a ketone to an alcohol; conversion of an esterto a ketone; interconversions of esters, acids and amides; alkylation,acylation and sulfonylation of alcohols and amines; and many others.Substituents can also be added using common reactions, such asalkylation, acylation, halogenation or oxidation. Such manipulations arewell-known in the art, and many reference works summarize procedures andmethods for such manipulations. Some reference works which givesexamples and references to the primary literature of organic synthesisfor many functional group manipulations, as well as othertransformations commonly used in the art of organic synthesis areMarch's Organic Chemistry, 5^(th) Edition, Wiley and Chichester, Eds.(2001); Comprehensive Organic Transformations, Larock, Ed., VCH (1989);Comprehensive Organic Functional Group Transformations, Katritzky et al.(series editors), Pergamon (1995); and Comprehensive Organic Synthesis,Trost and Fleming (series editors), Pergamon (1991). It will also berecognized that another major consideration in the planning of anysynthetic route in this field is the judicious choice of the protectinggroup used for protection of the reactive functional groups present inthe compounds described in this invention. Multiple protecting groupswithin the same molecule can be chosen such that each of theseprotecting groups can either be removed without removal of otherprotecting groups in the same molecule, or several protecting groups canbe removed using the same reaction step, depending upon the outcomedesired. An authoritative account describing many alternatives to thetrained practitioner is Greene and Wuts, Protective Groups in OrganicSynthesis, Wiley and Sons (1999).

Pharmacological Activity

Having regard to their modulation of CFTR activity, compounds of formula(I), in free or pharmaceutically acceptable salt form, hereinafteralternately referred to as “agents of the invention”, are useful in thetreatment of conditions which respond to the modulation of CFTRactivity, particularly conditions benefiting from mucosal hydration suchas cystic fibrosis.

Diseases mediated by modulation of CFTR activity, include diseasesassociated with the regulation of fluid volumes across epithelialmembranes. For example, the volume of airway surface liquid is a keyregulator of mucociliary clearance and the maintenance of lung health.The modulation of CFTR activity will promote fluid accumulation on themucosal side of the airway epithelium thereby promoting mucus clearanceand preventing the accumulation of mucus and sputum in respiratorytissues (including lung airways). Such diseases include respiratorydiseases, such as cystic fibrosis, primary ciliary dyskinesia, chronicbronchitis, chronic obstructive pulmonary disease (COPD), asthma,respiratory tract infections (acute and chronic; viral and bacterial)and lung carcinoma. Diseases mediated by modulation of CFTR activityalso include diseases other than respiratory diseases that areassociated with abnormal fluid regulation across an epithelium, perhapsinvolving abnormal physiology of the protective surface liquids on theirsurface, e.g., Sjögren's Syndrome, xerostomia (dry mouth) orkeratoconjunctivitis sire (dry eye). Furthermore, modulation of CFTRactivity in the kidney could be used to promote diuresis and therebyinduce a hypotensive effect.

Treatment in accordance with the invention may be symptomatic orprophylactic.

Asthma includes intrinsic (non-allergic) asthma and extrinsic (allergic)asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma,exercise-induced asthma, occupational asthma and asthma inducedfollowing bacterial infection. Treatment of asthma is also to beunderstood as embracing treatment of subjects, e.g., of less than 4 or 5years of age, exhibiting wheezing symptoms and diagnosed or diagnosableas “wheezy infants”, an established patient category of major medicalconcern and now often identified as incipient or early-phase asthmatics.(For convenience this particular asthmatic condition is referred to as“wheezy-infant syndrome”.)

Prophylactic efficacy in the treatment of asthma will be evidenced byreduced frequency or severity of symptomatic attack, e.g., of acuteasthmatic or bronchoconstrictor attack, improvements in lung function orimproved airways hyperreactivity. It may further be evidenced by reducedrequirement for other, symptomatic therapy, i.e., therapy for orintended to restrict or abort symptomatic attack when it occurs, e.g.,anti-inflammatory (e.g., cortico-steroid) or bronchodilatory.Prophylactic benefit in asthma may, in particular, be apparent insubjects prone to “morning dipping”. “Morning dipping” is a recognizedasthmatic syndrome, common to a substantial percentage of asthmatics andcharacterized by asthma attack, e.g., between the hours of about 4-6 am,i.e., at a time normally substantially distant from any previouslyadministered symptomatic asthma therapy.

Chronic obstructive pulmonary disease includes chronic bronchitis ordyspnea associated therewith, emphysema, as well as exacerbation ofairways hyperreactivity consequent to other drug therapy, in particular,other inhaled drug therapy. The invention is also applicable to thetreatment of bronchitis of whatever type or genesis including, e.g.,acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis.

Dry eye disease is characterized by a decrease in tear aqueousproduction and abnormal tear film lipid, protein and mucin profiles.There are many causes of dry eye, some of which include age, laser eyesurgery, arthritis, medications, chemical/thermal burns, allergies anddiseases, such as cystic fibrosis and Sjögren's Syndrome. Increasinganion secretion via CFTR would enhance fluid transport from the cornealendothelial cells and secretory glands surrounding the eye to increasecorneal hydration. This would help to alleviate the symptoms associatedwith dry eye disease.

Sjögren's Syndrome is an autoimmune disease in which the immune systemattacks moisture-producing glands throughout the body, including eye,mouth, skin, respiratory tissue, liver, vagina and gut. Symptoms includedry eye, dry mouth and dry vagina, as well as lung disease. The diseaseis also associated rheumatoid arthritis, systemic lupus, systemicsclerosis and polymypositis/dermatomyositis. Defective proteintrafficking is believed to cause the disease, for which treatmentoptions are limited. Modulators of CFTR activity may hydrate the variousorgans affected by the disease and help to alleviate the associatedsymptoms.

The suitability of CFTR activity modulators as a treatment of a diseasebenefiting from mucosal hydration may be tested by determining themovement of chloride ions in a suitable cell-based assay. For examplesingle cells or confluent epithelia, endogenously expressing orengineered to overexpress CFTR can be used to assess channel functionusing electrophysiological techniques or ion flux studies. See methodsdescribed in: Hirsh et al., J Pharm Exp Ther (2004); Moody et al., Am JPhysiol Cell Physiol (2005).

CFTR activity modulators, including the compounds of formula (I), arealso useful as co-therapeutic agents for use in combination with otherdrug substances, such as anti-inflammatory, bronchodilatory,antihistamine or anti-tussive drug substances, particularly in thetreatment of cystic fibrosis or obstructive or inflammatory airwaysdiseases such as those mentioned hereinbefore, e.g., as potentiators oftherapeutic activity of such drugs or as a means of reducing requireddosaging or potential side effects of such drugs.

The compounds of Formula (I), (II) or (III) may be mixed with the otherdrug substance in a fixed pharmaceutical composition or it may beadministered separately, before, simultaneously with or after the otherdrug substance.

Accordingly, the invention includes as a further aspect a combination ofa CFTR activity modulator with osmotic agents (hypertonic saline,dextran, mannitol, Xylitol), ENaC blockers, an anti-inflammatory,bronchodilatory, antihistamine, anti-tussive, antibiotic and/or DNasedrug substance, wherein the CFTR activity modulator and the further drugsubstance may be in the same or different pharmaceutical composition.

Suitable antibiotics include macrolide antibiotics, e.g., tobramycin(TOBI™).

Suitable DNase drug substances include dornase alfa (Pulmozyme™), ahighly-purified solution of recombinant human deoxyribonuclease I(rhDNase), which selectively cleaves DNA. Dornase alfa is used to treatcystic fibrosis.

Other useful combinations of CFTR activity modulators withanti-inflammatory drugs are those with antagonists of chemokinereceptors, e.g., CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8,CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5antagonists, such as Schering-Plough antagonists SC-351125, SCH-55700and SCH-D; Takeda antagonists, such asN-[[4-[[[6,7-dihydro-2-(4-methyl-phenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-amin-iumchloride (TAK-770); and CCR-5 antagonists described in U.S. Pat. No.6,166,037 (particularly claims 18 and 19), WO 00/66558 (particularlyclaim 8), WO 00/66559 (particularly claim 9), WO 04/018425 and WO04/026873.

Suitable anti-inflammatory drugs include steroids, in particular,glucocorticosteroids, such as budesonide, beclamethasone dipropionate,fluticasone propionate, ciclesonide or mometasone furoate, or steroidsdescribed in WO 02/88167, WO 02/12266, WO 02/100879, WO 02/00679(especially those of Examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60,67, 72, 73, 90, 99 and 101), WO 03/35668, WO 03/48181, WO 03/62259, WO03/64445, WO 03/72592, WO 04/39827 and WO 04/66920; non-steroidalglucocorticoid receptor agonists, such as those described in DE10261874, WO 00/00531, WO 02/10143, WO 03/82280, WO 03/82787, WO03/86294, WO 03/104195, WO 03/101932, WO 04/05229, WO 04/18429, WO04/19935 and WO 04/26248; LTD4 antagonists, such as montelukast andzafirlukast; PDE4 inhibitors, such as cilomilast (Ariflo®GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004(Bayer), SCH-351591 (Schering-Plough), Arofylline (AlmirallProdesfarma), PD189659/PD168787 (Parke-Davis), AWD-12-281 (Asta Medica),CDC-801 (Celgene), SelCID™ CC-10004 (Celgene), VM554/UM565 (Vernalis),T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo), and those disclosed in WO92/19594, WO 93/19749, WO 93/19750, WO 93/19751, WO 98/18796, WO99/16766, WO 01/13953, WO 03/104204, WO 03/104205, WO 03/39544, WO04/000814, WO 04/000839, WO 04/005258, WO 04/018450, WO 04/018451, WO04/018457, WO 04/018465, WO 04/018431, WO 04/018449, WO 04/018450, WO04/018451, WO 04/018457, WO 04/018465, WO 04/019944, WO 04/019945, WO04/045607 and WO 04/037805; adenosine A2B receptor antagonists such asthose described in WO 02/42298; and beta-2 adrenoceptor agonists, suchas albuterol (salbutamol), metaproterenol, terbutaline, salmeterolfenoterol, procaterol, and especially, formoterol, carmoterol andpharmaceutically acceptable salts thereof, and compounds (in free orsalt or solvate form) of formula (I) of WO 0075114, which document isincorporated herein by reference, preferably compounds of the Examplesthereof, especially indacaterol and pharmaceutically acceptable saltsthereof, as well as compounds (in free or salt or solvate form) offormula (I) of WO 04/16601, and also compounds of EP 1440966, JP05025045, WO 93/18007, WO 99/64035, USP 2002/0055651, WO 01/42193, WO01/83462, WO 02/66422, WO 02/70490, WO 02/76933, WO 03/24439, WO03/42160, WO 03/42164, WO 03/72539, WO 03/91204, WO 03/99764, WO04/16578, WO 04/22547, WO 04/32921, WO 04/33412, WO 04/37768, WO04/37773, WO 04/37807, WO 04/39762, WO 04/39766, WO 04/45618, WO04/46083, WO 04/80964, WO 04/108765 and WO 04/108676.

Suitable bronchodilatory drugs include anticholinergic or antimuscarinicagents, in particular, ipratropium bromide, oxitropium bromide,tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate, but alsothose described in EP 424021, U.S. Pat. No. 3,714,357, U.S. Pat. No.5,171,744, WO 01/04118, WO 02/00652, WO 02/51841, WO 02/53564, WO03/00840, WO 03/33495, WO 03/53966, WO 03/87094, WO 04/018422 and WO04/05285.

Suitable dual anti-inflammatory and bronchodilatory drugs include dualbeta-2 adrenoceptor agonist/muscarinic antagonists such as thosedisclosed in USP 2004/0167167, WO 04/74246 and WO 04/74812.

Suitable antihistamine drug substances include cetirizine hydrochloride,acetaminophen, clemastine fumarate, promethazine, loratidine,desloratidine, diphenhydramine and fexofenadine hydrochloride,activastine, astemizole, azelastine, ebastine, epinastine, mizolastineand tefenadine, as well as those disclosed in JP 2004107299, WO03/099807 and WO 04/026841.

In accordance with the foregoing, the invention also provides as afurther aspect a method for the treatment of a condition responsive tomodulation of CFTR activity, e.g., diseases associated with theregulation of fluid volumes across epithelial membranes, particularly anobstructive airways disease, which comprises administering to a subject,particularly a human subject, in need thereof a compound of formula (I),(II) or (III), in free form or in the form of a pharmaceuticallyacceptable salt.

In another aspect the invention provides a compound of formula (I), (II)or (III), in free form or in the form of a pharmaceutically acceptablesalt, for use in the manufacture of a medicament for the treatment of acondition responsive to modulation of CFTR activity, particularly anobstructive airways disease, e.g., cystic fibrosis and COPD.

The agents of the invention may be administered by any appropriateroute, e.g. orally, e.g., in the form of a tablet or capsule;parenterally, e.g., intravenously; by inhalation, e.g., in the treatmentof an obstructive airways disease; intranasally, e.g., in the treatmentof allergic rhinitis; topically to the skin; or rectally. In a furtheraspect, the invention also provides a pharmaceutical compositioncomprising a compound of formula (I), in free form or in the form of apharmaceutically acceptable salt, optionally together with apharmaceutically acceptable diluent or carrier therefor. The compositionmay contain a co-therapeutic agent, such as an anti-inflammatory,broncho-dilatory, antihistamine or anti-tussive drug as hereinbeforedescribed. Such compositions may be prepared using conventional diluentsor excipients and techniques known in the galenic art. Thus oral dosageforms may include tablets and capsules. Formulations for topicaladministration may take the form of creams, ointments, gels ortransdermal delivery systems, e.g., patches. Compositions for inhalationmay comprise aerosol or other atomizable formulations or dry powderformulations.

When the composition comprises an aerosol formulation, it preferablycontains, e.g., a hydro-fluoro-alkane (HFA) propellant, such as HFA134aor HFA227 or a mixture of these, and may contain one or more co-solventsknown in the art, such as ethanol (up to 20% by weight), and/or one ormore surfactants, such as oleic acid or sorbitan trioleate, and/or oneor more bulking agents, such as lactose. When the composition comprisesa dry powder formulation, it preferably contains, e.g., the compound offormula (I), (II) or (III) having a particle diameter up to 10 microns,optionally together with a diluent or carrier, such as lactose, of thedesired particle size distribution and a compound that helps to protectagainst product performance deterioration due to moisture, e.g.,magnesium stearate. When the composition comprises a nebulisedformulation, it preferably contains, e.g., the compound of formula (I),(II) or (III) either dissolved, or suspended, in a vehicle containingwater, a co-solvent, such as ethanol or propylene glycol and astabilizer, which may be a surfactant.

Further aspects of the invention include:

-   -   (a) a compound of formula (I), (II) or (III) in inhalable form,        e.g., in an aerosol or other atomisable composition or in        inhalable particulate, e.g., micronised form;    -   (b) an inhalable medicament comprising a compound of formula        (I), (II) or (III) in inhalable form;    -   (c) a pharmaceutical product comprising a compound of        formula (I) in inhalable form in association with an inhalation        device; and    -   (d) an inhalation device containing a compound of formula        (I), (II) or (III) in inhalable form.

Dosages of compounds of formula (I), (II) or (III) employed inpracticing the present invention will of course vary depending, e.g., onthe particular condition to be treated, the effect desired and the modeof administration. In general, suitable daily dosages for administrationby inhalation are of the order of 0.005-10 mg, while for oraladministration suitable daily doses are of the order of 0.05-100 mg.

Pharmaceutical Use and Assay

Compounds of formula (I), (II) or (III) and their pharmaceuticallyacceptable salts, hereinafter referred to alternatively as “agents ofthe invention”, are useful as pharmaceuticals. In particular, thecompounds are suitable CFTR activity modulators and may be tested in thefollowing assays.

Membrane Potential Assay

CFTR activity can be quantified by measuring the transmembranepotential. The means for measuring the transmembrane potential in abiological system can employ a number of methods includingelectrophysiological and optical fluorescence-based membrane potentialassays.

The optical membrane potential assay utilises a negatively chargedpotentiometric dye, such as the FLIPR membrane potential dye (FMP) (seeBaxter D F, Kirk M, Garcia A F, Raimondi A, Holmqvist M H, Flint K K,Bojanic D, Distefano P S, Curtis R, Xie Y. ‘A novel membranepotential-sensitive fluorescent dye improves cell-based assays for ionchannels.’ J Biomol Screen. 2002 February; 7(1):79-85) which whenextracellular is bound to a quenching agent. Upon cellulardepolarisation the negatively charged dye redistributes to theintracellular compartment, unbinding from the membrane impermeant quenchagent, yielding an increase in fluorescence. This change in fluorescenceis proportional to the change in transmembrane potential which canresult from the activity of CFTR. The changes in fluorescence can bemonitored in real time by an appropriately equipped fluorescencedetector such as the FLIPR (fluorometric imaging plate reader) in 96 or384-well microtitre plates.

Cell Culture:

Chinese hamster ovary (CHO) cells stably expressing the ΔF508-CFTRchannel were used for membrane potential experiments. Cells weremaintained at 37° C. in 5% v/v CO₂ at 100% humidity in Modified Eaglesmedium (MEM) supplemented with 8% v/v foetal calf serum, 100 μg/mlmethotrexate and 100 U/ml penicillin/streptomycin. Cells were grown in225 cm² tissue culture flasks. For membrane potential assays cells wereseeded into 96 well plates at 40,000 cells per well, allowed to adhereand then maintained at 26° C. for 48 h to facilitate channel insertion.

Potentiator Assay:

The membrane potential screening assay utilised a low chloride ioncontaining extracellular solution (˜5 mM) combined with a doubleaddition protocol. The first addition was of buffer with or without testcompound followed 5 minutes later by an addition of forskolin (1-20μM)—this protocol favours maximum chloride efflux in response toΔF508-CFTR activation. The ΔF508-CFTR mediated chloride ion efflux leadsto a membrane depolarisation which is optically monitored by the FMPdye.

Solutions:

Low chloride extracellular (mM): 120 Na-gluconate, 1.2 CaCl₂, 3.3KH₂PO₄, 0.8 K₂H PO₄, 1.2 MgCl₂, 10.0 D-glucose, 20.0 HEPES, pH 7.4 withNaOH FMP dye: made up as per manufacturers' instructions in low chlorideextracellular solution detailed above, at 10× final concentration, andstored as 1 mL aliquots at −20° C.

IonWorks Quattro assay:

CFTR activity can also be quantified electrophysiologically using thewhole-cell configuration of the patch clamp technique (Hamill et alPflugers Archive 1981). This assay directly measures the currentsassociated with chloride flow through CFTR channels whilst eithermaintaining or adjusting the transmembrane voltage. This assay can useeither single glass micropipettes or parallel planar arrays to measureCFTR activity from native or recombinant cell systems. Currents measuredusing parallel planar arrays can be quantified using an appropriatelyequipped instrument such as the IonWorks Quattro (Molecular Devices) orthe Qpatch (Sophion). The Quattro system can measure CFTR currents fromeither a single cell per recording well (HT configuration) oralternatively from a population of 64 cells per well (Population PatchClamp PPC) (Finkel A, Wittel A, Yang N, Handran S, Hughes J, CostantinJ. ‘Population patch clamp improves data consistency and success ratesin the measurement of ionic currents.’ J Biomol Screen. 2006 August;11(5):488-96).

Cell Culture:

Chinese hamster ovary (CHO) cells stably expressing the ΔF508-CFTRchannel were used for IonWorks Quattro experiments. Cells weremaintained at 37° C. in 5% v/v CO₂ at 100% humidity in D-MEMsupplemented with 10% (v/v) FCS, 100 U/mL Penicillin/Streptomycin, 1%(v/v) NEAA, 1 mg/ml Zeocin and 500 ug/ml Hygromycin B. For experimentscells were grown in 225 cm² tissue culture flasks until near confluenceand then cultured at 26° C. for 48-72 h to facilitate channel insertion.Cells were removed from the flask and resuspended in eitherextracellular recording solution for immediate experimentation oralternatively in growth medium supplemented with 10% v/v DMSO and frozento −80° C. as 1-2 mL aliquots for use at a later date.

Potentiator Assay:

Cells, at a density of 1.5-3 million per mL, were placed on the Quattrosystem, added to the planar patch array and seals allowed to establishfor 5-10 mins. After assessing seal resistances (commonly >50 MΩ),whole-cell access was obtained by perforation with 100 μg/mLamphotericin B. Baseline currents were measured by a pre-compound scanobtained by application of a voltage ramp from −100 to +100 mV. This wasfollowed by addition of either buffer or test compound diluted in theextracellular solution supplemented with 20 μM forskolin, to each of the384 wells of the planar parch array. After incubation step (5-20minutes) the post-compound currents were measured again by applicationof a voltage ramp from −100 to +100 mV. The difference in currentsbetween the pre- and post-compound scans defined the efficacy of CFTRpotentiation.

Solutions:

Extracellular solution (ECS): 145 mM NaCl, 4 mM CsCl, 5 mM D-glucose, 10mM TES, 1 mM CaCl₂, 1 mM MgCl₂, pH 7.4 NaOH

Intracellular buffer (ICS): 113 mM L-Aspartic acid, 113 mM CsOH, 27 mMCsCl, 1 mM NaCl, 1 mM MgCl₂, 1 mM EGTA, 10 mM TES. pH 7.2 with CsOH.Filter sterilized before use.

Ion Transport Assay:

Another method to measure CFTR function is Ussings chamber short circuitcurrent measurement. Engineered or native epithelial cells are grown toconfluent monolayer on a semi-permeable filter and sandwiched betweentwo perspex blocks. The flow of chloride ions via CFTR from one side ofthe epithelia to the other can be quantified by measuring the flow ofcurrent whilst maintaining the transepithelial potential at 0 mV. Thisis achieved using KCl filled agar-based electrodes to both clamp thecellular monolayer and measure the flow of currents.

Cell Culture:

FRT cells stably expressing ΔF508-CFTR were cultured on plastic inCoon's modified F-12 medium supplemented with 32 mM NaHCO₃, 10% v/vfetal bovine serum, 2 mM L-glutamine, 100 U/mL penicillin, 100 μg/mLstreptomycin and 30 μg/mL hygromycin B as the growth medium. For Ussingchamber experiments, the cells were grown as polarized epithelia onSnapwell permeable support inserts (500000 cells/insert in growthmedium) and cultured for 7 to 9 days. The inserts were fed with freshCoon's modified F-12 growth medium every 48 hours, and 24 hours prior toUssing chamber experiment. To increase the ΔF508 CFTR protein expressionat the cell surface, plates were incubated at 27° C. for 48 h beforeperforming an Ussing chamber experiment.

Potentiator Assay:

Fischer Rat Thyroid (FRT) epithelial cells, stably expressing humanΔF508-CFTR were used as monolayer cultures on permeable supports. Cl⁻current was measured using the short circuit current technique, under animposed basolateral to apical Cl⁻ gradient in Ussing chambers. Tomeasure stable Cl⁻ currents, FRT cells were cultured for 48 h at 27° C.to facilitate the insertion of ΔF508 CFTR into the plasma membrane.Ussing chamber studies were likewise conducted at 27° C. Under theseconditions, the effects of cumulative additions of test compounds onΔF508 CFTR currents could be quantitated with both potency and efficacyendpoints. Compounds were added to both the apical and basloalteralsides subsequent to addition of 10 μM forskolin. Efficacy of compoundswas compared to a known potentiator such as gensitein.

Solutions:

Basolateral Ringer solution (mM): 126 NaCl, 24 NaHCO₃, 0.38 KH₂PO₄, 2.13K₂HPO₄, 1 MgSO₄, 1 CaCl₂ and 10 glucose.

Apical Ringer solution (mM): 140 Na-gluconate, 1 MgSO₄, 2 CaCl₂, 1 HCl,10 glucose and 24 NaHCO₃.

Compounds can also be tested for their ability to stimulate insertion ofΔF508 CFTR into the cell membrane using the above assays. For theseassays the protocols were identical other than cells were not culturedat low temperature (26 or 27° C.) but instead incubated with testcompounds for 12-24 h prior to assay.

Compounds of the Examples, herein below, generally have EC₅₀ values inthe data measurements described above below 10 μM. Table 1 provides alist of representative compounds with their EC₅₀ value.

TABLE 1 Example No EC₅₀ μM 2 0.015 3 0.055 4 0.076 5 0.05 6 0.426 70.040 8 0.060 9 0.090 10 0.112 11 0.037 12 0.035 14 0.115 15 0.051 160.008 17 0.010

Compounds listed below are within the scope of the broadest claim andthe CFTR EC₅₀ values in the data measurements described above were above5 μM:

-   3-amino-6-bromo-N-(imidazo[1,2-a]pyridin-2-ylmethyl)-5-(trifluoromethyl)pyrazine-2-carboxamide;-   3-amino-6-bromo-N-((1-methyl-1H-imidazol-4-yl)methyl)-5-(trifluoromethyl)pyrazine-2-carboxamide;-   2-(3-amino-6-bromo-5-(trifluoromethyl)picolinamido)acetic acid;-   3-amino-6-bromo-N-((1-methyl-1H-pyrazol-3-yl)methyl)-5-(trifluoromethyl)pyrazine-2-carboxamide;-   3-amino-N-(2-(4-fluorophenyl)-2-oxoethyl)-6-(1-methyl-1H-indol-6-yl)-5-(trifluoromethyl)picolinamide;-   3-amino-6-bromo-N-((1-methyl-1H-imidazol-2-yl)methyl)-5-(trifluoromethyl)pyrazine-2-carboxamide;-   6-((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)-3-(2,5-dimethyl-1H-pyrrol-1-yl)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide;-   3-amino-6-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-N-(2-(4-fluorophenyl)-2-oxoethyl)-5-(trifluoromethyl)pyrazine-2-carboxamide;-   (R)-3-amino-6-bromo-N-((4-methylpiperazin-2-yl)methyl)-5-(trifluoromethyl)pyrazine-2-carboxamide;-   3-amino-6-bromo-N-((1-methyl-1H-imidazol-5-yl)methyl)-5-(trifluoromethyl)pyrazine-2-carboxamide;-   3-amino-6-(3-(N,N-dimethylsulfamoyl)phenyl)-N-(2-(4-fluorophenyl)-2-oxoethyl)-5-(trifluoromethyl)picolinamide;-   3-amino-6-bromo-N-isobutyl-N-methyl-5-(trifluoromethyl)pyrazine-2-carboxamide;-   3-amino-6-bromo-N-((1-methyl-1H-pyrazol-5-yl)methyl)-5-(trifluoromethyl)pyrazine-2-carboxamide;-   6-bromo-3-(methylamino)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide;-   (3-amino-6-bromo-5-(trifluoromethyl)pyrazin-2-yl)(4-methylpiperazin-1-yl)methanone;-   3-amino-6-bromo-N-(2-(pyridin-4-yl)ethyl)-5-(trifluoromethyl)pyrazine-2-carboxamide;-   3-amino-N-(2-(4-fluorophenyl)-2-oxoethyl)-6-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-(trifluoromethyl)picolinamide;-   3-amino-6-(4-carbamoyl-2-methylphenyl)-N-(2-(4-fluorophenyl)-2-oxoethyl)-5-(trifluoromethyl)picolinamide;-   3-amino-6-bromo-N-(2-(pyridin-3-yl)ethyl)-5-(trifluoromethyl)pyrazine-2-carboxamide;-   3-amino-6-(3,4-dimethylphenyl)-N-(2-(4-fluorophenyl)-2-oxoethyl)-5-(trifluoromethyl)picolinamide;-   3-amino-N-benzyl-6-bromo-N-methyl-5-(trifluoromethyl)pyrazine-2-carboxamide;-   3-amino-6-hydroxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide;-   3-amino-6-hydroxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide;-   (3-amino-6-bromo-5-(trifluoromethyl)pyrazin-2-yl)(4-methyl-3-phenylpiperazin-1-yl)methanone;-   (S)-3-amino-6-bromo-N-((1-ethylpyrrolidin-2-yl)methyl)-5-(trifluoromethyl)pyrazine-2-carboxamide;    and-   3-amino-6-bromo-N-(imidazo[1,5-a]pyridin-1-ylmethyl)-5-(trifluoromethyl)pyrazine-2-carboxamide.

The invention is illustrated by the following Examples.

EXAMPLES General Conditions

Mass spectra were run on LC-MS systems using electrospray ionization.These were either Agilent 1100 HPLC/Micromass Platform Mass Spectrometercombinations or Waters Acquity HPLC with SQD Mass Spectrometer. [M+H]⁺refers to mono-isotopic molecular weights.

NMR spectra were run on open access Bruker AVANCE 400 NMR spectrometersusing ICON-NMR. Spectra were measured at 298K and were referenced usingthe solvent peak.

Optical rotations were measured at 589 nm and 546 nm using an Opticalactivity AA-1000 polarimeter at 21° C.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, preferably between about 15 mm Hg and100 mm Hg (=20-133 mbar). The structure of final products, intermediatesand starting materials is confirmed by standard analytical methods,e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, andNMR. Abbreviations used are those conventional in the art. If notdefined, the terms have their generally accepted meanings.

ABBREVIATIONS

-   app apparent-   ATP adenosine 5′-triphosphate-   BI NAP racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl-   BOC tertiary butyl carboxy-   br broad-   d doublet-   dd doublet of doublets-   DCM dichloromethane-   DIEA diethylisopropylamine-   DIPEA diisopropylethylamine-   DMF N,N-dimethylformamide-   DMSO dimethylsulfoxide-   DTT dithiothreitol-   ESI electrospray ionization-   EtOAc ethyl acetate-   eq equivalent-   h hour(s)-   HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate-   HPLC high pressure liquid chromatography-   IR infrared spectroscopy-   LCMS liquid chromatography and mass spectrometry-   MeOH methanol-   MS mass spectrometry-   MW microwave-   m multiplet-   min minutes-   ml milliliter(s)-   m/z mass to charge ratio-   NMR nuclear magnetic resonance-   ppm parts per million-   PS polymer supported-   rac racemic-   RT room temperature-   Rt retention time-   s singlet-   SCX-2 strong cation exchange (e.g. Isolute® SCX-2 columns from    Biotage)-   t triplet-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran

Referring to the examples that follow, compounds of the preferredembodiments were synthesized using the methods described herein, orother methods, which are known in the art.

The various starting materials, intermediates, and compounds of thepreferred embodiments may be isolated and purified, where appropriate,using conventional techniques such as precipitation, filtration,crystallization, evaporation, distillation, and chromatography. Unlessotherwise stated, all starting materials are obtained from commercialsuppliers and used without further purification. Salts may be preparedfrom compounds by known salt-forming procedures.

It should be understood that the organic compounds according to thepreferred embodiments may exhibit the phenomenon of tautomerism. As thechemical structures within this specification can only represent one ofthe possible tautomeric forms, it should be understood that thepreferred embodiments encompasses any tautomeric form of the drawnstructure.

If not indicated otherwise, the analytical HPLC conditions are asfollows:

Method 10 min LC_v001 Column Waters BEH C18 100 × 2.1 mm, 1.7 μm Column50° C. Temp. Eluents A: H₂O, B: acetonitrile, both containing 0.1% TFAFlow Rate 0.7 ml/min Gradient 0.25 min 5% B; 5% to 95% B in 7.75 min,1.00 min 95% B Method 10 min LC_v002 Column Waters BEH C18 50 × 2.1 mm,1.7 μm Column 50° C. Temperature Eluents A: H₂O, B: methanol, bothcontaining 0.1% TFA Flow Rate 0.8 ml/min Gradient 0.20 min 5% B; 5% to95% B in 7.80 min, 1.00 min 95% B Method 10 min LC_v003 Column WatersBEH C18 50 × 2.1 mm, 1.7 μm Column 50° C. Temperature Eluents A: H₂O, B:acetonitrile, both containing 0.1% TFA Flow Rate 0.8 ml/min Gradient0.20 min 5% B; 5% to 95% B in 7.80 min, 1.00 min 95% B Method 2 minLC_v001 Column Waters BEH C18 100 × 2.1 mm, 1.7 μm Column 50° C. Temp.Eluents A: H₂O, B: acetonitrile, both containing 0.1% TFA Flow Rate 0.7ml/min Gradient 0.25 min 5% B; 5% to 95% B in 1.00 min, 0.25 min 95% BMethod 2 min LC_v002 Column Waters BEH C18 50 × 2.1 mm, 1.7 μm Column50° C. Temperature Eluents A: H₂O, B: methanol, both containing 0.1% TFAFlow Rate 0.8 ml/min Gradient 0.20 min 5% B; 5% to 95% B in 1.30 min,0.25 min 95% B Method 2 min LC_v003 Column Waters BEH C18 50 × 2.1 mm,1.7 μm Column 50° C. Temperature Eluents A: H₂O, B: acetonitrile, bothcontaining 0.1% TFA Flow Rate 0.8 ml/min Gradient 0.20 min 5% B; 5% to95% B in 1.30 min, 0.25 min 95% B Method 10 min C18 Column: Gemini C18100 × 3 mm, 3 micron Column 50° C. Temperature Eluents: A: H2O, B:Methanol, 0.1% formic acid Flow rate: 1 ml/min Gradient: 0.00 min 0% B,10.00 min 95% B Method AD25IPA_DEA Mobile 25% isopropanol + 0.1% v/vDEA/75% CO₂ Phase: Column: Chiralpak AD-H, 250 × 10 mm id, 5 μmDetection: UV @ 220 nm Flow rate: 10 ml/min

Example compounds of the present invention include

Preparation of Final Compounds Example 1.03-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid(3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide

3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid(Intermediate A) (397 mg, 1.392 mmol),3-amino-1,1,1-trifluoro-2-methyl-propan-2-ol hydrochloride (250 mg,1.392 mmol) and HATU (529 mg, 1.392 mmol) were dissolved in DMF (10 ml)and stirred at RT for 2 min. 4-Methylmorpholine (0.413 ml, 4.18 mmol)was added and stirring continued at RT for 3 h. The reaction mixture waspoured onto ice/water (100 ml) and extracted with EtOAc (250 ml). Theorganic extract was washed with sat NH₄Cl solution (˜50 ml), dried overMgSO₄ and concentrated in vacuo to give a pale brown oil. The oil wasdissolved in CHCl₃ (˜3 ml) and loaded onto a 24 g ISCO (silica) columneluting with iso-hexane:EtOAc to afford the title product; LC-MS Rt=1.46mins; [M+H]⁺410.1, Method 2 minLC_v002. ¹H NMR (400 MHz, DMSO-d6) δ 8.30(NH, t), 7.72 (1H, s), 7.29 (NH2, b s), 6.28 (OH, s), 3.68 (1H, dd),3.47 (1H, dd), 1.24 (3H, s). ¹⁹F NMR (400 MHz, DMSO-d6) δ −62.71 (CF3,s), −80.48 (CF3, s).

The compounds of the following tabulated Examples (Table 2) wereprepared by a similar method to that of Example 1 from the appropriatestarting compound and amine. Single enantiomers were prepared by usingchiral amines or by separation of the product by Supercritical FluidChromatography. The preparations of the starting compounds and aminesare described in the Intermediates section, unless they are commerciallyavailable. DIPEA or TEA may have been used in place of4-methylmorpholine in some reactions.

TABLE 2 Retention Time, [M + H]⁺, Ex. Structure Name 1H NMR 1.1

3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid((R)-3,3,3-trifluoro- 2-hydroxy-propyl)- amide (Separated by SFC, secondeluted peak) R.t 3.26 mins; Method = AD25IPA_DEA 1H NMR (DMSO) δ 3.4(1H, m), 3.6 (1H, m), 4.3 (1H, m), 6.5 (1H, s), 7.3 (2H, s), 7.7 (1H,s), 8.6 (1H, t), 1.2

3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid(3,3,3-trifluoro-2- hydroxy-propyl)-amide (Racemate) Rt 1.42 mins; [M +H]⁺ 398 Method: 2minLC_v002 1H NMR (DMSO) δ 3.4 (1H, m), 3.6 (1H, m),4.3 (1H, m), 6.5 (1H, d), 7.3 (2H, s), 7.7 (1H, s), 8.6 (1H, t), 1.3

3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid((S)-3,3,3- trifluoro-2-hydroxy- propyl)-amide Prepared using (S)-3-Amino-1,1,1-trifluoro- propan-2-ol Rt 1.41 mins; [M + H]⁺ 398 Method:2minLC_v002 1H NMR (DMSO) δ 3.4 (1H, m), 3.6 (1H, m), 4.3 (1H, m), 6.5(1H, d), 7.3, (2H, s), 7.7 (1H, s), 8.6 (1H, t) 1.4

3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid [(R)-1-(tetrahydro-furan-2- yl)methyl]-amide Prepared using (R)-(−)-tetrahydrofurfuryl amine Rt 1.51 mins; [M + H]⁺ 370 Method: 2minLC_v0021H NMR (DMSO) δ 1.6 (1H, m), 1.9, (3H, m), 3.4, (2H, m), 3.7, (1H, m),3.8, (1H, m), 4.1, (1H, m), 7.3, (2H, s), 7.7, (1H, s), 8.4, (1H, t) 1.5

3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid([1,3]dioxolan-2- ylmethyl)-amide Rt 1.42 mins; [M + H]⁺ 370 Method:2minLC_v002 1H NMR (DMSO) δ 3.4, (2H, t), 3.8, (2H, m), 3.9, (2H, m),5.0, (1H, t), 7.3, (2H, br), 7.7, (1H, s), 8.4, (1H, t), 1.6

3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid [(S)-1-(tetrahydro-furan-2- yl)methyl]-amide Prepared using (S)- (+)-Tetrahydrofurfurylamine Rt 1.52 mins; [M + H]⁺ 370 Method: 2minLC_v002.1H NMR (DMSO) 1.6, (1H, m), 1.9, (3H, m), 3.3, (2H, m), 3.6, (1H, m),3.8, (1H, m), 4.0, (1H, m), 7.4, (2H, s), 7.7, (1H, s), 8.4, (1H, d) 1.7

3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid(tetrahydro-furan- 2-ylmethyl)-amide Rt 1.49 mins; [M + H]⁺ 368 Method:2minLC_v002. 1H NMR (DMSO) δ 1.55, (1H, m), 1.8, (3H, m), 3.3, (2H, m),3.6, (1H, m), 3.8, (1H, m), 4.0, (1H, m), 7.3, (2H, s), 7.7, (1H, s),8.4, (1H, t) 1.8

3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid(2-methyl-2- piperidin-1-yl-propyl)- amide Rt 1.14 mins; [M + H]⁺ 423Method: 2minLC_v002 1H NMR (DMSO) δ 1.3, (6H, s), 1.4, (1H, m), 1.7,(3H, m), 1.9, (2H, m), 2.9, (2H, m), 3.6, (2H, m), 3.7, (2H, m), 7.3,(2H, s), 7.7, (1H, s), 8.7, (1H, t) 1.9

3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid(2-hydroxy- propyl)-amide Rt 4.06 mins; [M + H]⁺ 344. Method:10minLC_v002 1H NMR. ([400 MHz], [DMSO- d6]) δ 8.30 (1H, t), 7.69 (1H,s), 7.28 (2H, br s), 4.84 (1H, d), 3.78 (1H, m), 3.29 (1H, m), 3.14 (1H,m), 1.05 (3H, d). 1.10

3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid(2-hydroxy-2- methyl-propyl)-amide Rt 4.35 mins; [M + H]⁺ 338. Method:10minLC_v002 1H NMR. ([400 MHz], [DMSO- d6]) δ 8.14 (1H, t), 7.70 (1H,s), 7.29 (2H, br s), 4.70 (1H, s), 3.24 (1H, d), 1.10 (6H, s). 1.11

3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid(2-methyl- tetrahydro-furan-2- ylmethyl)-amide Rt 1.53 mins; [M + H]⁺384 Method: 2minLC_v002. 1H NMR. ([400 MHz], [DMSO- d6]) δ 8.12 (1H, t),7.70 (1H, s), 7.28 (2H, br s), 3.76 (2H, t), 3.33 (2H, d), 1.88 (2H, m),1.80 (1H, m), 1.60 (1H, m), 1.13 (3H, s). 1.12

3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid(2-methoxy- ethyl)-amide Rt 1.43 mins; [M + H]⁺ 342; Method:2minLC_v002. 1H NMR. ([400 MHz], [DMSO- d6]) 

 8.41 (1H, t), 7.69 (1H, s), 7.28 (2H, br s), 3.44 (4H, m), 3.27 (3H,s). 1.13

3-Amino-6-bromo-5- trifluoromethyl- pyrazine-2-carboxylic acid(2-methyl- tetrahydro-furan-2- ylmethyl)-amide Rt 1.52 mins; [M + H]⁺385; Method: 2minLC_v002. 1H NMR. ([400 MHz], [DMSO- d6]) 

 8.35 (1H, t), 8.09 (2H, br s), 3.76 (2H, t), 3.34 (2H, d), 1.86 (3H,m), 1.58 (1H, m), 1.13 (3H, s). 1.14

3-Amino-6-bromo-5- trifluoromethyl- pyrazine-2-carboxylic acid[2-(4-fluoro- phenyl)-2-morpholin- 4-yl-ethyl]-amide Rt 4.29 mins; [M +H]⁺ 492. Method: 10minLC_v002. ¹H NMR (400 MHz, MeOD) δ_(H) 7.61-7.64(2H, m, 2 × Ar′H (AA′BB′X system)), 7.28-7.32 (2H, m, 2 × Ar′H (AA′BB′Xsystem)), 4.65-4.73 (1H, br m, NHCH_(A)H_(B)CH_(X) N (Ar′)), 4.31 (1H,dd_(ABX), J = 6.5/14.4 Hz, NHCH_(A) H_(B)CH_(X)N(Ar′)), 3.70- 4.14 (6H,m, NHCH_(A) H_(B)CH_(X)N (Ar′) + 5 × morpholine CH), 3.00-3.30 (3H, m, 3× morpholine CH). 1.15

3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid[2-(4-fluoro- phenyl)-2-morpholin- 4-yl-ethyl]-amide Rt 4.39 mins; [M +H]⁺ 491 Method: 10minLC_v002. ¹H NMR (400 MHz, MeOD) δ_(H) 8.37-8.38(1H, m, ArC(O)NHCH₂), 7.68 (1H, s, ArH-1), 7.35 (2H, m (AA′BB′X system),2 × Ar′H-2), 7.17-7.25 (4H, br s + m (AA′BB′X system), ArNH₂ + 2 ×Ar′H-3), 3.73-3.81 (2H, m, NHCH _(A)H_(B)CH(N)Ar′ +NHCH_(A)H_(B)CH(N)Ar′), 3.53- 3.58 (5H, morpholine 2 × CH₂ + NHCH_(A) H_(B)CH(N)Ar′), 2.34- 2.43 (4H, m, 2 × morpholine CH₂). 1.16

3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid(2-morpholin-4-yl- 2-phenyl-ethyl)-amide Rt 4.20 mins; [M + H]⁺ 473Method 10minLC_v002. 1H NMR (400 MHz, DMSO- d6) δ 8.46 (1H, s broad),7.70 (1H, s), 7.32 (7H, m broad), 3.75 (2H, m broad), 3.59 (4H, broad),2.40 (2H, broad), 2.30 (2H, broad). 1.17

3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid (2-dimethylamino-2- phenyl-ethyl)-amide Rt 4.25 mins; [M + H]⁺ 431; Method;10minLC_v002. 1H NMR (400 MHz, DMSO- d6) δ 10.20 (1H, s), 8.72 (1H, t),7.71 (1H, s), 7.60 (2H, s broad), 7.50 (3H, s broad) 7.30 (2H, s broad),4.67 (1H, m), 4.19 (1H, qui), 3.83 (m), 2.80 (3H, d), 2.61 (3H, d). 1.18

3-Amino-6-bromo-5- trifluoromethyl- pyrazine-2-carboxylic acid(3-methyl-2- morpholin-4-yl-butyl)- amide Rt 3.39 mins; [M + H]⁺ 442.Method 10minLC_v002. 1H NMR (400 MHz, DMSO- d6) δ 9.03 (1H, s), 9.10(1H, s), 8.12 (2H, s), 4.00-3.20 (12H, broad), 1.10 (3H, broad), 1.00(3H, broad). 1.19

3-Amino-6-bromo-5- trifluoromethyl- pyrazine-2-carboxylic acid(2-methyl-2- morpholin-4-yl-propyl)- amide Rt 2.83 mins; [M + H]⁺ 428;Method 10minLC_v002. 1H NMR (400 MHz, DMSO- d6) δ 9.04 (1H, s), 8.95(1H, s), 8.10 (2H, s), 4.04 (2H, d), 3.75 (2H, t), 3.60 (4H + broadwater signal underneath), 3.20 (2H, q), 1.35 (6H, s). 1.20

3-Amino-6-bromo-5- trifluoromethyl- pyrazine-2-carboxylic acid(1-morpholin-4-yl- cyclohexylmethyl)- amide Rt 3.59 mins; [M + H]⁺ 466.Method 10minLC_v002. 1H NMR (400 MHz, DMSO- d6) δ 9.00 (1H, broad), 8.90(1H, broad), 8.10 (1H, s), 4.02- 3.35 (20H, very broad) 1.21

3-Amino-6-bromo-5- trifluoromethyl- pyrazine-2-carboxylic acid(2-morpholin-4-yl- 2-phenyl-ethyl)-amide Rt 6.09 mins; [M + H]⁺ 474Method 10minC18 1.22

3-Amino-6-bromo-5- trifluoromethyl- pyrazine-2-carboxylic acid (2-dimethylamino-2- phenyl-ethyl)-amide Rt 5.42 mins; [M + H]⁺ 432 Method10minC18 1.23

3-Amino-6-bromo-5- trifluoromethyl- pyrazine-2-carboxylic acid[2-(4-methoxy- phenyl)-2-pyrrolidin-1- yl-ethyl]-amide Rt 5.64 mins;[M + H]⁺ 488 Method 10minC18 1.24

3-Amino-6-bromo-5- trifluoromethyl- pyrazine-2-carboxylic acid[2-dimethylamino- 2-(4-methoxy-phenyl)- ethyl]-amide Rt 5.51 mins; [M +H]⁺ 462; Method 10minC18 1.25

3-Amino-6-(4-fluoro- phenyl)-5- trifluoromethyl- pyridine-2-carboxylicacid (3,3,3-trifluoro-2- hydroxy-2-methyl- propyl)-amide Rt 5.41 mins;[M + H]⁺ 426; Method 10minLC_v002. ¹H NMR δ 8.42 (1H, m), 7.72 (1H, s),7.5 (2H, m), 7.3 (2H, t), 7.22 (2H, br s), 6.24 (1H, s), 3.68 (1H, m),3.46 (1H, m), 1.24 (3H, s) 1.26

3-Amino-5- trifluoromethyl- pyridine-2-carboxylic acid(3,3,3-trifluoro-2- hydroxy-2-methyl- propyl)-amide Rt 4.18 mins; [M +H]⁺ 332; Method 10minLC_v002. ¹H NMR δ 8.58 (1H, t), 8.1 (1H, s), 7.56(1H, s), 7.2 (2H, br s), 6.29 (1H, s), 3.61-3.7 (1H, m), 3.42-3.5 (1H,m), 1.26 (3H, s). 1.27

3-Amino-6-(4-chloro- 2-methyl-phenyl)-5- trifluoromethyl-pyridine-2-carboxylic acid ((R)-3,3,3- trifluoro-2-hydroxy-propyl)-amide Prepared using (R)-3- amino-1,1,1- trifluoropropan-2-ol Rt1.59 mins; [M + H]⁺ 442 Method: 2minLC_v002. 1H NMR. ([400 MHz], [DMSO-d6]) δ 8.54 (1H, br), 7.69 (1H, s), 7.41 (1H, d), 7.30 (1H, dd), 7.24(2H, br s), 7.20 (1H, d), 6.40 (1H, br), 4.19 (1H, m), 3.54 (1H, m),3.36 (1H, m), 2.01 (3H, s). 1.28

3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid(3,3,3-trifluoro-2- hydroxy-2- trifluoromethyl-propyl)- amide Rt 1.59mins; [M + H]⁺ 466; Method 2minLC_v002. ¹H NMR (400 MHz, DMSO- d6) δ8.50 (1H, t), 8.30 (1H, s), 7.72 (1H, s), 7.30 (2H, s), 4.00 (2H, d)1.29

5-Amino-6′-methyl-3- trifluoromethyl- [2,3′]bipyridinyl-6- carboxylicacid (3,3,3- trifluoro-2-hydroxy-2- methyl-propyl)-amide Rt 1.16 mins;[M + H]⁺ 423; Method 2minLC_v002. ¹H NMR (400 MHz, DMSO- d6) δ 8.53 (1H,d), 8.45 (1H, t), 7.75 (1H, d), 7.71 (1H, s), 7.34 (1H, d), 7.25 (2H,s), 6.21 (1H, s), 3.69 (1H, dd), 3.42 (1H, dd), 2.54 (3H, s), 1.22 (3H,s). 1.30

Methyl 3-(3-amino-6- bromo-5- (trifluoromethyl) picolinamido)propanoate.Rt 4.64 mins; [M + H]⁺ 372.1; Method 10minLC_v002. ¹H NMR (400 MHz,DMSO- d6) δ 8.56 (1H, t), 7.68 (1H, s), 7.27 (2H, br s), 3.61 (3H, s)3.50 (2H, q), 2.60 (2H, t). 1.31

3-Amino-N- (benzo[d]isoxazol-3- ylmethyl)-6-bromo-5- (trifluoromethyl)picolinamide Rt 4.18 mins; [M + H]⁺ 417.1; Method 10minLC_v002. ¹H NMR(400 MHz, DMSO- d6) δ 9.32 (NH, t), 7.96 (1H, dt), 7.74 (1H, dt), 7.70(1H, s), 7.65-7.62 (1H, m), 7.40- 7.36 (1H, m), 7.29 (NH2, b s), 4.88(2H, d) 1.32

3-Amino-6-(oxazol-2- yl)-N-(3,3,3-trifluoro-2- hydroxy-2-methylpropyl)-5- (trifluoromethyl) picolinamide Rt 3.44 mins; [M + H]⁺399.1; Method 10minLC_v003. 1.33

Single enantiomer of 3-Amino-6-bromo-N- (3,3,3-trifluoro-2- methoxy-2-methylpropyl)-5- (trifluoromethyl) picolinamide (Separated by SFC,second eluted peak) 1H NMR (400 MHz, DMSO- d6) δ 8.24 (1H, t), 7.72 (1H,s), 7.29 (2H, s), 3.65 (2H, m), 3.37 (3H, s), 1.35 (3H, s) 1.34

Single enantiomer of 3-amino-N-(2-hydroxy- 3-methyl-2-(trifluoromethyl)butyl)- 6-methoxy-5- (trifluoromethyl) picolinamide(Separated by SFC, first eluted peak) Rt 4.48 mins; [M + H]⁺ 390.3;Method 10minLC_v003. ¹H NMR (400 MHz, DMSO- d6) δ 8.21 (1H, m), 7.69(1H, s), 6.59 (2H, s), 6.26 (1H, s), 3.91 (3H, s), 3.68 (2H, m), 2.02(1H, m), 1.02 (6H, m) 1.35

3-Amino-6- cyclopropyl-N-(3,3,3- trifluoro-2-hydroxy-2- methylpropyl)-5-(trifluoromethyl) picolinamide Rt 1.23 mins; [M + H]⁺ 372.2; Method2minLC_v003. ¹H NMR (400 MHz, DMSO- d6) δ 8.29 (1H, m), 7.56 (1H, s),6.9 (2H, br s), 6.3 (1H, s), 3.62 (1H, m), 3.48 (1H, m), 2.1 (1H, m),1.24 (3H, s), 0.9-1.1 (4H, m) 1.36

3-Amino-6-methoxy- N-(3,3,3-trifluoro-2- hydroxy-2-(trifluoromethyl)propyl)- 5-(trifluoro methyl) picolinamide Rt 4.27mins; [M + H]⁺ 416.3; Method 10minLC_v003. ¹H NMR (400 MHz, DMSO-d6) δ8.39 (1H, t), 8.32 (1H, br s), 7.69 (1H, s), 6.70 (2H, br s), 3.99 (2H,d), 3.93 (3H, s), 1.37

Single enantiomer of 5-amino-N-(3,3,3- trifluoro-2-hydroxy-2-methylpropyl)-3- (trifluoromethyl)-2,4′- bipyridine-6- carboxamide(Separated by SFC, first eluted peak) Rt 0.86 mins; [M + H]⁺ 409.1;Method 2minLC_v003. ¹H NMR (400 MHz, DMSO-d6) δ 8.70 (2H, d), 8.45 (1H,t), 7.75 (1H, s), 7.50 (2H, d), 7.33 (2H, s), 6.22 (1H, s), 3.69 (1H,dd), 3.43 (1H, dd), 1.21 (3H, s). 1.38

3-Amino-6-bromo-5- trifluoromethyl- pyridine-2-carboxylic acid(3-methyl-2-oxo- butyl)-amide Rt 1.18 mins; [M + H]⁺ 368; Method2minLC_v003. ¹H NMR (400 MHz, DMSO-d6) δ 8.64 (1H, t), 7.71 (1H, s),7.29 (2H, broad s), 4.2 (2H, d), 2.7-2.8 (1H, m), 1.08 (6H, d, 2 × CH3).1.39

3-Amino-6-bromo-5- trifluoromethyl- pyrazine-2-carboxylic acid[2-(4-fluoro- phenyl)-2-oxo-ethyl]- amide ¹H NMR (400 MHz, DMSO-d6) δ9.0 (1H, t, NH), 8.1 (4H, m, NH2, Ar—H), 7.4 (2H, t, Ar—H), 4.8 (2H, 5,CH2)

Example 2 and 3

These compounds namely,3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide. (Ex. 2)

and 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide. (Ex. 3)

are prepared by chiral separation of3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid(3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide. (Example 1) usingSupercritical Fluid Chromatography under the following conditions:

Mobile Phase: 12% isopropanol+0.1% DEA/88% CO₂

Column: Chiralpak OJ-H, 250×10 mm id, 5 μm

Detection: UV@220 nm

Flow rate: 10 ml/min

Sample concentration: 347 mg in 5 ml EtOH.

Injection volume: 50 μl

Example 2

First eluted peak:3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide.

LC-MS: Rt=4.97 min [M+H]+ 410.1/412.2 (Method 10 minLC_v002).

1H NMR (400 MHz, DMSO-d6) δ 8.30 (NH, t), 7.72 (1H, s), 7.29 (NH2, b s),6.28 (OH, s), 3.68 (1H, dd), 3.47 (1H, dd), 1.24 (3H, s)

¹⁹F NMR (400 MHz, DMSO-d6) d −62.70 (CF₃, s), −80.47 (CF3, s)

Optical rotation [α]²¹ _(D) at 589 nm+14.4° (c=0.522, MeOH).

Example 3

Second eluted peak:3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide.

LC-MS Rt=4.94 min [M+H]+ 412.1 (Method 10 minLC_v002).

1H NMR (400 MHz, DMSO-d6) δ 8.30 (NH, t), 7.72 (1H, s), 7.29 (NH2, b s),6.28 (OH, s), 3.68 (1H, dd), 3.47 (1H, dd), 1.24 (3H, s)

¹⁹F NMR (400 MHz, DMSO-d6) d −62.70 (CF₃, s), −80.48 (CF₃, s).

The stereochemistry of this compound was confirmed by X-raycrystallography.

Example 4, 5 and 6

This compound namely,3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid(3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide. (Ex. 4),

was prepared according to the following procedure:

A solution comprising3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid(Intermediate D)(4 g, 16.94 mmol) and3-amino-1,1,1-trifluoro-2-methylpropan-2-ol hydrochloride (IntermediateR) (3.04 g, 16.94 mmol) in NMP (188 ml) was treated with HATU (7.73 g,20.33 mmol) followed by dropwise addition (2 ml portions) of DIPEA (8.88ml, 50.8 mmol) over 1 hour. After stirring for a further hour, thereaction mixture was poured into water (450 ml) and EtOAc (450 ml). Theaqueous phase was acidified with 5M HCl (50 ml) and the layers wereseparated. The organic portion was washed with 2M NaOH (200 ml), water(4×200 ml), brine (2×100 ml), dried over MgSO₄, filtered andconcentrated in vacuo to afford a brown solid. Purification of the solidby chromatography on silica (220 g pre-packed silica cartridge) elutingwith 0-50% EtOAc in iso-hexane afforded the racemate,3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid(3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide (Ex. 4) as a yellowsolid;

1H NMR (400 MHz, DMSO-d6) δ 8.3 (1H, t), 7.7 (1H, s), 6.7 (2H, s), 6.2(1H, s), 3.9 (3H, s), 3.7 (1H, m), 3.5 (1H, m), 1.2 (3H, s).

LC-MS: Rt 1.24 min; MS m/z 362.4 [M+H]+; Method 2 minLC_v003.

Chiral separation of the racemate by Supercritical Fluid Chromatographywas carried out using the following conditions to afford the compoundslisted hereinafter:

Mobile Phase: 12% 2-propanol+0.1% DEA/50% CO₂

Column: Chiralcel OD-H, 250×10 mm id, 5 μm (2 columns linked in series)

Detection: UV@ 220 nm

Flow rate: 10 ml/min

Sample concentration: 3.5 g in 30 ml EtOH

Injection volume: 100 μl

Examples 5 and 6 are entantiomers.

Example 5

First eluted peak Rt=7.30 minutes.3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide:

1H NMR (400 MHz, DMSO-d6) δ 8.3 (1H, t), 7.6 (1H, s), 6.6 (2H, broad),6.2 (1H, s), 3.9 (3H, s), 3.6 (1H, m), 3.5 (1H, m), 1.3 (3H, s);

LC-MS Rt=1.15 mins, [M+H]+ 362.4 (Method 2 minLC_v003).

Optical rotation [α]²¹ _(D) at 589 nm −20.83° (c=0.513, MeOH).

The stereochemistry of this compound was confirmed by X-raycrystallography.

Example 6

Second eluted peak Rt=8.29 minutes.3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide

1H NMR (400 MHz, DMSO-d6) δ 8.3 (1H, t), 7.6 (1H, s), 6.6 (2H, broad),6.2 (1H, s), 3.9 (3H, s), 3.6 (1H, m), 3.5 (1H, m), 1.3 (3H, s);

LC-MS Rt=1.15 mins [M+H]+ 362.4 (Method 2 minLC_v003).

Alternatively, Example 5 may be prepared according to the followingmethod:

To a solution of3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid(Intermediate D) (10 g, 42.3 mmol) and(S)-3-amino-1,1,1-trifluoro-2-methylpropan-2-ol hydrochloride(Intermediate RA)(7.60 g, 42.3 mmol) in NMP (400 ml) was added HATU(19.3 g, 50.8 mmol) followed by dropwise addition of DIPEA (22.19 ml,127 mmol) over ˜1 hr. After stirring at room temperature for 30 min, themixture was added to EtOAc (2 L), washed with 1M NaOH (2×1 L), water (1L), brine (1 L), dried (MgSO₄) and evaporated under reduced pressure togive the crude product as a dark brown oil. Purification bychromatography on silica eluting with a gradient of 1 to-25% of EtOAc iniso-hexane afforded a yellow oil. Recrystallisation of the oil fromiso-hexane/DCM afforded3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide as a crystallinesolid;

¹H NMR (400 MHz, DMSO-d6) δ 8.28 (1H, t), 7.66 (1H, s), 6.67 (2H, s),6.27 (1H, s), 3.91 (3H, s), 3.65 (1H, m), 3.45 (1H, m), 1.24 (3H, s).

¹⁹F NMR (376 MHz, DMSO-d6)−62.58 ppm (s), −80.43 ppm (s)

Example 73-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide

A mixture comprising3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide (Ex. 3)(100 mg,0.244 mmol), 4-fluorophenylboronic acid (37.5 mg, 0.268 mmol) and 1,1′bis(diphenylphosphoshio) ferrocenepalladium dichloride (19.90 mg, 0.024mmol) was suspended in THF (2 ml) and 1M Cs₂CO₃ (0.667 ml). The vial wasflushed with N₂, sealed and heated at 160° C. using microwave radiationfor 15 minutes. The mixture was partitioned between EtOAc (50 ml) andwater (50 ml). The organic portion was separated and washed with brine(30 ml), dried (MgSO₄), filtered through Celite® (filter material) andconcentrated in vacuo. The crude residue was dissolved in DMSO (2 ml)and purified by mass directed LCMS using MeCN/Water/0.1% TFA eluent toafford clean product. The product fraction obtained as MeCN/Water/0.1%TFA solution was poured into EtOAc (50 ml) and washed with saturatedNaHCO₃ (50 ml) to free base the product. The organic portion werecombined, dried (MgSO₄) and concentrated in vacuo to afford the titlecompound as a pale orange crystalline solid; 1H NMR (400 MHz, DMSO-d6) δ8.4 (1H, m), 7.7 (1H, s), 7.49 (2H, m), 7.29 (2H, t), 7.2 (2H, br s),6.22 (1H, s), 3.68 (1H, m), 3.44 (1H, m), 1.22 (3H, s); LC-MS Rt 4.41mins [M+H]+ 426 (Method 10 minLC_v003).

Example 83-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide

This compound was prepared from3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide (Ex. 2)analogously to Example 8. 1H NMR (400 MHz, DMSO-d6) δ 8.42 (1H, m), 7.7(1H, s), 7.5 (2H, m), 7.3 (2H, t), 7.21 (2H, br s), 6.24 (1H, s), 3.68(1H, m), 3.44 (1H, m), 1.22 (3H, s); LC-MS Rt=4.39 mins [M+H]+ 426(Method 10 minLC_v003).

Example 9 and 10

The enantiomers of3-amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylicacid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide were preparedfrom3-Amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylicacid (Intermediate H) and 3-amino-1,1,1-trifluoro-2-methylpropan-2-olhydrochloride analogously to Example 1 and separated by chiralseparation using Supercritical Fluid Chromatography:

Example 9

First eluted peak. Entantiomer 1 of3-Amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylicacid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide:

1H NMR (400 MHz, DMSO-d6) δ 8.38 (t, 1H), 7.83 (s, 1H), 7.78 (s, 1H),7.60 (d, 1H), 7.54 (d, 1H), 7.39 (br s, 2H), 6.25 (br s, 1H). 3.71 (dd,1H), 3.48 (dd, 1H), 1.26 (s, 3H); LC-MS Rt=1.65 mins [M+H]+ 476 (Method2 minLC_v002).

Example 10

Second Eluted peak. Enantiomer 2 of3-Amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylicacid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide.

1H NMR (400 MHz, DMSO-d6) δ 8.38 (t, 1H), 7.83 (s, 1H), 7.78 (s, 1H),7.60 (d, 1H), 7.54 (d, 1H), 7.39 (br s, 2H), 6.25 (br s, 1H). 3.71 (dd,1H), 3.48 (dd, 1H), 1.26 (s, 3H); LC-MS Rt 1.65 mins [M+H]+=476.1(Method 2 minLC_v002).

Example 113-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid(2-hydroxy-2-methyl-propyl)-amide

To a stirred suspension of3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid(2-hydroxy-2-methyl-propyl)-amide (Ex. 1.10) (180 mg, 0.505 mmol) and4-fluorophenylboronic acid (106 mg, 0.758 mmol) in a 2:1 mixture oftoluene:EtOH (12 ml) under nitrogen was added 2M Na₂CO₃(aq) (1.011 ml,2.022 mmol) followed by Pd(dppf)Cl₂.CH₂Cl₂ adduct (41 mg, 0.051 mmol).The reaction mixture was heated using microwave radiation at 140° C. for1 hour and then allowed to cool to RT. The mixture was diluted withEtOAc (100 ml) and washed with water (100 ml). The organic phase wasseparated, filtered through Celite® (filter material) dried (MgSO₄) andconcentrated in vacuo to yield a brown oil/solid. Purification bychromatography on silica eluting with MeOH/DCM yielded a yellowoil/solid. This was passed through a 500 mg Isolute® Si-TMT cartridge(2,4,6-trimercaptotriazine silica, pre-wetted with DCM) eluting with 30%MeOH/DCM (50 ml) to afford a yellow oil/solid. The crude product wasdried in vacuo and slurried in ˜0.5 ml DCM. The resulting suspension wasremoved by filtration and the filtrate was evaporated to yield the titlecompound as a light yellow/brown foam-like solid; LC-MS Rt=5.30 mins[M+H]+ 372 (Method 10 minLC_v002).

1H NMR (400 MHz, DMSO-d6), δ 8.29 (1H, t), 7.69 (1H, s), 7.49 (2H, t),7.29 (2H, t), 7.22 (2H, s), 4.63 (1H, s), 3.24 (2H, d), 1.08 (6H, s).

Example 12 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylicacid (3,3,3-trifluoro-2-hydroxy-propyl)-amide

Step 1:3-(2,5-Dimethyl-pyrrol-1-yl)-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylicacid (3,3,3-trifluoro-2-hydroxy-propyl)-amide

This compound was prepared from3-(2,5-Dimethyl-pyrrol-1-yl)-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylicacid (Intermediate D2) and 3-amino-1,1,1-trifluoropropan-2-olanalogously to Example 1; LC-MS Rt=1.50 mins [M+H]+ 426 (Method 2minLC_v002).

Step 2: 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid(3,3,3-trifluoro-2-hydroxy-propyl)-amide

3-(2,5-Dimethyl-pyrrol-1-yl)-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylicacid (3,3,3-trifluoro-2-hydroxy-propyl)-amide (350 mg, 0.823 mmol) wasdissolved in EtOH (14 ml) and water (7 ml). Hyroxylamine hydrochloride(572 mg, 8.23 mmol) was added followed by TEA (167 mg, 1.646 mmol) andthe mixture was heated at reflux overnight. After cooling the RT, themixture was purified by reverse phase chromatography eluting with MeOH;water (0.1% TFA) to afford the title compound as a pale yellow solid;LC-MS Rt=4.20 min [M+H]+ 348.2 (Method 10 minLC_v002)

1H NMR (400 MHz, DMSO-d6) δ 8.47 (NH, t), 7.66 (1H, s), 6.68 (NH2, b s),6.51 (OH, d), 4.27-4.20 (1H, m), 3.93 (3H, s), 3.64-3.58 (1H, m),3.44-3.37 (1H, m)

19F NMR (400 MHz, DMSO-d6) d −62.67 (CF₃, s), −77.05 (CF3, s), TraceTFA.

Example 145-Amino-6′-methyl-3-trifluoromethyl-[2,3′]bipyridinyl-6-carboxylic acid(3,3,3-trifluoro-2-hydroxy-2-trifluoromethyl-propyl)-amide

This compound was prepared from3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid(3,3,3-trifluoro-2-hydroxy-2-trifluoromethyl-propyl)-amide (Ex. 1.28)and 2-methylpyridine-5-boronic acid analogously to Example 8. LC-MS Rt1.28 min; 477 [M+H]+; (Method 2 minLC_v002); ¹H NMR (400 MHz, MeOD) δ8.50 (1H, s), 7.85 (1H, dd), 7.69 (1H, s), 7.40 (1H, d), 4.00 (2H, s),2.62 (3H, s).

Example 155-Amino-6′-methyl-3-trifluoromethyl-[2,3′]bipyridinyl-6-carboxylic acid(3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide

This compound was prepared by chiral separation of5-amino-6′-methyl-3-trifluoromethyl-[2,3]bipyridinyl-6-carboxylic acid(3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide (Example 1.29) usingSupercritical Fluid Chromatography; LC-MS Rt 3.15 min [M+H]+ 423;(Method 10 minLC_v002); 1H NMR (400 MHz, DMSO-d6) δ 8.53 (1H, s), 8.49(1H, t), 7.75 (1H, d), 7.71 (1H, s), 7.35 (1H, d), 7.25 (2H, s), 6.22(1H, s), 3.69 (1H, dd), 3.42 (1H, dd), 2.54 (3H, s), 1.22 (3H, s). SFCRetention Time: 4.87 min.

Example 16 and 17 3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylicacid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide and3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide

Step 1:3-(2,5-Dimethyl-pyrrol-1-yl)-5,6-bis-trifluoromethyl-pyridine-2-carboxylicacid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide

To a stirred solution of3-(2,5-dimethyl-pyrrol-1-yl)-5,6-bis-trifluoromethyl-pyridine-2-carboxylicacid (Intermediate M) (1.16 g, 3.29 mmol) in NMP (32 ml) was added3-Amino-1,1,1-trifluoro-2-methyl-propan-2-ol hydrochloride (commerciallyavailable) (591 mg, 3.29 mmol) followed by HATU (1.25 g, 3.29 mmol) andNEt₃ (918 ul, 6.59 mmol) and the reaction mixture was left to stir atRT. After 1 h a further 0.2 equiv. NEt₃ was added. After 15 min afurther 0.4 equiv. NEt₃ and 0.2 equiv. amine were added. After 30 min afurther 0.1 equiv HATU was added. After 30 min most of the startingmaterial had been consumed. The reaction mixture was added to EtOAc (50ml), washed with 0.1M NaOH and the aqueous layer was back extracted withEtOAc (2×50 ml). The combined organic extracts were washed with water(2×150 ml), brine (100 ml), dried (MgSO₄) and concentrated in vacuo togive the crude product as an orange oil.

The crude material was purified by chromatography on silica eluting with0-15% EtOAc in iso-hexane to afford the title product as a yellow solid;LC-MS Rt 1.32 min; MS m/z 478.2 [M+H]+; Method 2 minLC_v003.

Step 2: 3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid(3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide

To a stirred solution of3-(2,5-dimethyl-pyrrol-1-yl)-5,6-bis-trifluoromethyl-pyridine-2-carboxylicacid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide (985 mg, 2.064mmol) in 2:1 EtOH/H₂O (7.5 ml) was added hydroxylamine hydrochloride(1.43 g, 20.64 mmol) followed by NEt₃ (575 ml, 4.13 mmol). The reactionmixture was heated to reflux (˜98° C.) for 11.5 hours and then allowedto cool to RT. The solvent was removed in vacuo and the resultingresidue was partitioned between EtOAc (25 ml) and water (25 ml). Theaqueous layer was separated and extracted with EtOAc (2×25 ml) and thecombined organic extracts were washed with brine (50 ml), dried (MgSO₄)and concentrated in vacuo. The crude material was purified bychromatography on silica eluting with 0-25% EtOAc in iso-hexane toafford the title product as a pale yellow solid; LC-MS: Rt 1.24 min; MSm/z 400.0 [M+H]+; Method 2 minLC_v003.

Step 3: 3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide and3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide

These compounds were prepared by chiral separation of3-amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid(3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; Enantiomer 1: LC-MSRt 1.23 min; MS m/z 400.0 [M+H]+; Method 2 minLC_v003. SFC RetentionTime 5.07 min.

Enantiomer 2: LC-MS Rt 1.23 min; MS m/z 400.0 [M+H]+; Method 2minLC_v003. SFC Retention Time 5.13 min.

Example 183-Amino-6-methoxy-N-(3,3,3-trifluoro-2-(4-methoxybenzylamino)-2-methylpropyl)-5-(trifluoromethyl)picolinamide

The title compound was prepared analogously to Example 1 from3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid(Intermediate D) and3,3,3-trifluoro-N2-(4-methoxybenzyl)-2-methylpropane-1,2-diamine(Intermediate N). DIPEA was used in this reaction. 1H NMR (400 MHz,DMSO-d6) δ 8.27 (1H, m), 7.68 (1H, s), 7.25 (2H, d), 6.83 (2H, d), 6.70(2H, s), 3.85 (3H, s), 3.75 (2H, m), 3.72 (3H, s), 3.70 (1H, m), 3.47(1H, m), 2.80 (1H, t), 1.24 (3H, s)

Example 193-Amino-N-(2-amino-3,3,3-trifluoro-2-methylpropyl)-6-methoxy-5-(trifluoromethyl)

A mixture comprising3-amino-6-methoxy-N-(3,3,3-trifluoro-2-(4-methoxybenzylamino)-2-methylpropyl)-5-(trifluoromethyl)picolinamide(Ex. 18) (0.9 g, 1.873 mmo) in TFA (50 ml) was heated to 50° C. for 2 h.After cooling to RT, the pH was adjusted to pH 12 using 2M NaOH. Theproduct was extracted with DCM and the organic extract was washed withwater, dried over MgSO₄ and concentrated in vacuo. The crude product wasloaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 inMeOH. The methanolic ammonia fractions were concentrated in vacuo anddried under vacuum to afford the title compound. 1H NMR (400 MHz,DMSO-d6) δ 8.35 (1H, m), 7.67 (1H, s), 6.67 (2H, s), 3.93 (3H, s), 3.58(1H, m), 3.40 (1H, m), 2.22 (2H, s), 1.14 (3H, s). LC-MS Rt 0.94 min; MSm/z 361.2 [M+H]+; Method 2 minLC_v003.

Example 203-Amino-6-(pyrrolidin-1-yl)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide

Step 1:3-(2,5-Dimethyl-1H-pyrrol-1-yl)-6-(pyrrolidin-1-yl)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide

The title compound was prepared from Intermediate DA analogously toExample 1; LC-MS Rt 1.42 min; MS m/z 479.3 [M+H]+; Method 2 minLC_v003.

Step 2:3-Amino-6-(pyrrolidin-1-yl)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide

This compound was prepared from3-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(pyrrolidin-1-yl)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamideanalogously to Intermediate D (final step). The resulting racemate wasseparated by SFC to afford the title compound; First eluted peak:

1H NMR (400 MHz, DMSO-d6) δ 8.24 (1H, m), 7.6 (1H, s), 6.4 (2H, br s),6.32 (1H, s), 3.64 (1H, m), 3.48 (1H, m), 3.35 (4H), 1.88 (4H, m), 1.25(3H, s); LC-MS Rt 3.87 min; MS m/z 401.3 [M+H]+; Method 10 minLC_v003.

Example 21(S)-3-amino-6-ethoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide

The title compound was prepared from Intermediate DB and Intermediate Ranalogously to Example 20; 1H NMR (400 MHz, DMSO-d6) δ 8.3 (1H, t), 7.7(1H, s), 6.6 (2H, broad), 6.3 (1H, s), 4.4 (2H, q), 3.6 (1H, mult), 3.5(1H, mult), 1.3 (3H, t), 1.2 (3H, s).

LC-MS Rt 1.20 min; MS m/z 376.2 [M+H]+; Method 2 minLC_v003.

Example 223-Amino-6-bromo-N-(2-morpholinoethyl)-5-(trifluoromethyl)pyrazine-2

To a stirred solution of3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid(Intermediate C) (250 mg, 0.874 mmol) in NMP (8 ml) was added4-(2-aminoethyl)morphonline (138 ul, 1.049 mmol) followed by DIPEA (763ul, 4.37 mmol). To this solution was then added HATU (499 mg, 1.311mmol) in portions and the reaction mixture was left to stir at RT for 1hour. A further 1 equiv. of 4-(2-aminoethyl)morphonline was added. Aftera further 1.5 hr, 0.5 equiv. HATU (166 mg, 0.425 mmol) was added and theRM was left to stir for a further 30 min. The mixture was added to EtOAc(50 ml) and washed with 0.1M NaOH (50 ml). The aqueous layer was backextracted with EtOAc (50 ml). The combined organics were washed withwater (50 ml), brine (50 ml), dried over magnesium sulfate andevaporated under reduced pressure to give a brown oil (418 mg). Thecrude product was purified by chromatography (Biotage-silica 20 g/70 mlcolumn, 3:1 EtOAc/iso-hexane). The resulting yellow residue was loadedonto an SCX-2 cartridge (10 g) that had been pre-wetted with MeOH. Thecartridge was washed with MeOH (140 ml) and eluted with 3.5M ammonia inmethanol solution (70 ml). The appropriate fractions were evaporatedunder reduced pressure to give a solid. This solid was dissolved inEtOAc and filtered under vacuum. The filtrate was evaporated underreduced pressure and then dried in vacuo to afford the title compound asa yellow solid;

LC-MS: Rt 2.61 min; MS m/z 398.2 [M+H]+; Method 10 minLC_v002

1H NMR (400 MHz, DMSO-d6) δ 8.70 (1H, s), 8.10 (2H, s), 3.58 (4H, t),3.40 (2H, q), 2.45 (2H, m), 2.40 (4H, s).

Example 23N-(2-(1H-imidazol-2-yl)propyl)-3-amino-6-bromo-5-(trifluoromethyl)pyrazine-2-carboxamide

The title compound was prepared from3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid(Intermediate C) and 2-(1H-imidazol-2-yl)propan-1-amine (preparedaccording to the procedure of Steffens, Robert; Schunack, Walter.Histamine analogs, XXVI. Racemic histamine H1-agonists. Archiv derPharmazie (Weinheim, Germany) (1984), 317(9), 771-6; 1H NMR (400 MHz,DMSO-d6) δ 11.8 (1H, s), 9.0 (1H, t), 8.1 (2H, s), 7.0 (1H, s), 6.8 (1H,s), 3.55 (2H, m), 3.15 (1H, m), 1.2 (3H, d). LC-MS [M+H]+ 393.0/395.1

Example 24a and 24b Enantiomers of3-amino-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5,6-bis(trifluoromethyl)pyrazine-2-carboxamide

The title compound was prepared from Intermediate BA and3-amino-1,1,1-trifluoro-2-methylpropan-2-ol analogously to Example 4.Chiral separation of the racemate by Supercritical Fluid Chromatographyafforded the title compound;

Example 24a

First eluted peak: Enantiomer 1 of3-amino-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5,6-bis(trifluoromethyl)pyrazine-2-carboxamide;

1H NMR (400 MHz, DMSO-d6) δ 8.61-8.74 (1H, broad hump), 8.5-8.61 (1H,broad hump), 8.46 (1H, t), 6.3 (1H, s), 3.69 (1H, m), 3.5 (1H, m), 1.29(3H, s)

LC-MS: Rt 4.23 min; MS m/z 401.2 [M+H]+; Method 10 minLC_v003.

Example 24b

Second eluted peak: Enantiomer 2 of3-amino-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5,6-bis(trifluoromethyl)pyrazine-2-carboxamide;

1H NMR (400 MHz, DMSO-d6) δ 8.61-8.76 (1H, broad hump), 8.5-8.60 (1H,broad hump), 8.46 (1H, t), 6.3 (1H, s), 3.69 (1H, m), 3.5 (1H, m), 1.29(3H, s)

LC-MS: Rt 4.24 min; MS m/z 401.2 [M+H]+; Method 10 minLC_v003. Opticalrotation [α]²¹ _(D) at 589 nm+22.0° (c=0.517, MeOH).

Example 253-Amino-6-(1-methyl-1H-pyrazol-4-yl)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide

Step 1:3-Amino-6-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)picolinic acid

3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methylester (Intermediate A4) (500 mg, 1.672 mmol), PdCl₂(dppf).CH₂Cl₂ adduct(205 mg, 0.251 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(383 mg, 1.839 mmol) and Cs₂CO₃ (6.69 ml, 6.69 mmol) in THF (12 ml)under N₂, was heated using microwave radiation at 150° C. for 10minutes. 2M NaOH (5 ml) was added and the mixture was stirred at RTovernight. The mixture was filtered through Celite® (filter material)and the organic solvent was removed. The resulting aqueous layer waswashed with EtOAc and acidified to pH1. The product was extracted withDCM and concentrated in vacuo to afford the title compound;

Step 2;3-Amino-6-(1-methyl-1H-pyrazol-4-yl)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide

The title compound was prepared from3-amino-6-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoro methyl)picolinic acidand 3-amino-1,1,1-trifluoro-2-methylpropan-2-ol analogously to Example 41H NMR (400 MHz, Methanol-d4) δ 7.97 (1H, s), 7.85 (1H, s), 7.60 (1H,s), 3.97 (3H, s), 3.77 (1H, m), 3.56 (1H, m), 1.37 (3H, s)

LC-MS: Rt 3.22 min; MS m/z 412.3 [M+H]+; Method 10 minLC_v003.

Example 26 3-Amino-6-furan-2-yl-5-trifluoromethyl-pyrazine-2-carboxylicacid [2-(2-methoxy-phenyl)-ethyl]-amide

The title compound was prepared from3-amino-6-furan-2-yl-5-trifluoromethyl-pyrazine-2-carboxylic acid(Intermediate PA) and the appropriate amine; MS m/z 406.93 [M+H]+

Preparation of Intermediates Intermediate A3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid

Intermediate A1: 2-Bromo-3-nitro-5-trifluoromethyl-pyridine

3-Nitro-5-(trifluoromethyl)pyridin-2-ol (31.00 g, 149 mmol) wasdissolved in acetonitrile (250 ml) to give a dark brown solution.Phosphorus(V) oxybromide (85 g, 298 mmol) was added and the mixture washeated at reflux for 4.5 hours and then stirred at RT overnight. Thereaction mixture was quenched by pouring into vigorously stirring water(600 ml) containing sodium hydrogencarbonate (110 g). The dark brownmixture was extracted with DCM (3×200 ml) and the organic phase waswashed with water (200 ml) and brine (100 ml), dried (MgSO₄) andconcentrated in vacuo to afford the title product as a brown oil.¹H-NMR: [400 MHz, CDCl₃, δ_(H), 8.87 (1H, d, J=1.4 Hz, ArH), 8.39 (1H,d, J=1.9 Hz, ArH).

Intermediate A2: 3-Nitro-5-trifluoromethyl-pyridine-2-carbonitrile

2-Bromo-3-nitro-5-trifluoromethyl-pyridine (10.00 g, 36.87 mmol) wasdissolved in toluene (250 ml) with stirring to give a pale yellowsolution. Tetrabutylammonium bromide (11.90 g, 36.9 mmol) was addedfollowed by copper(I) cyanide (9.92 g, 111 mmol) and the mixture washeated at reflux for 10 h. After cooling to RT, the reaction mixture waspartitioned between water (750 ml) and EtOAc (750 ml). The organicfractions were combined, washed with water (2×250 ml) and brine (100ml), dried (MgSO₄) and concentrated in vacuo to afford the titleproduct. ¹H-NMR: [400 MHz, DMSO-d₆ δ_(H) 9.55 (1H, m, ArH), 9.24 (1H, m,ArH)

Intermediate A3: 3-Amino-5-trifluoromethyl-pyridine-2-carboxylic acidmethyl ester

3-Nitro-5-trifluoromethyl-pyridine-2-carbonitrile (6.5 g, 29.9 mmol) wasdissolved in EtOAc (150 ml) to give a pale yellow solution and placedunder an atmosphere of nitrogen. 10% Palladium on activated carbon (3.19g, 2.99 mmol) was added and the reaction mixture stirred under anatmosphere of hydrogen for 18 hours. The reaction mixture was filteredand concentrated in vacuo. The crude residue was dissolved in HCl conc.(45 ml) and heated to reflux for 24 hours. The reaction mixture wasallowed to cool to RT and concentrated in vacuo. The solid was dissolvedin MeOH (300 ml) and sulfuric acid (14.4 ml) was added. The resultingsolution was heated at reflux for 48 hours. The reaction was allowed tocool to RT, then neutralised by addition of 10% NaHCO_(3(aq)) (600 ml).The product was extracted into DCM (3×200 ml) and the combined organicphases were washed with water (200 ml), brine (50 ml), (MgSO₄) andconcentrated in vacuo. The resulting solid was purified bychromatography on silica: Eluant gradient: isohexane (500 ml), 10% EtOAcin isohexane (1000 ml), 20% EtOAc in isohexane (1500 ml) to afford thetitled compound as a pale yellow solid ¹H-NMR: [400 MHz, DMSO-d₆, δ_(H)8.13 (1H, d, J=1.7 Hz, ArH), 7.60 (1H, d, J=1.3 Hz, ArH), 7.01 (2H, br,NH₂), 3.85 (3H, s, ArOCH₃), m/z 221.1 [M+H]⁺

Intermediate A4: 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylicacid methyl ester

3-Amino-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (9.49g, 43.16 mmol) was suspended in water (300 ml). Sulfuric acid (4.60 ml,86 mmol) was added followed by dropwise addition over 30 minutes of asolution of bromine (2.222 ml, 43.1 mmol) in acetic acid (29.6 ml, 517mmol). The reaction mixture was stirred at RT for 18 hours. A further100 ml of water was added, followed by a further 0.25 equivalents of thebromine/AcOH mixture (550 μL bromine in 7.4 ml AcOH) and the reactionmixture stirred at RT for an additional 90 minutes. The reaction mixturewas diluted with 500 ml water and neutralised by addition of solidNaHCO₃ (˜85 g). The suspension was extracted with DCM (3×300 ml) and thecombined organic phases washed with sat.NaHCO_(3(aq)) (250 ml), water(250 ml) and brine (100 ml), dried (MgSO₄) and concentrated in vacuo.The crude material was recrystallised from boiling MeOH (˜300 ml) togive the title product as a pale orange solid m/z 301.0 [M+H]⁺¹H-NMR:[400 MHz, DMSO-d₆ δ_(H) 7.77 (1H, s, ArH), 7.17 (2H, s, NH₂), 3.86 (3H,s, ArCO₂CH₃).

Intermediate A: 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylicacid

3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methylester (1.40 g, 4.68 mmol) was suspended in MeOH (15 ml); Sodiumhydroxide (2.0 M aqueous solution) (14.04 ml, 28.1 mmol) was added andthe suspension was stirred at RT overnight. The mixture was concentratedin vacuo and the resulting residue was dissolved in water (100 ml) andthen acidifed by the addition of 5.0M HCl(aq). The product was extractedinto ethyl acetate (2×75 ml) and the combined organic extracts werewashed with water (50 ml), brine (25 ml), dried (MgSO₄) and concentratedin vacuo to afford the title product as a yellow solid. ¹H-NMR: [400MHz, DMSO-d₆, δ_(H) 13.24 (1H, br s, CO₂H), 7.74 (1H, s, ArH), 7.17 92H,br s ArN H₂). m/z 285.1, 287.1 [M+H]⁺

Intermediate B 3-Amino-5-trifluoromethyl-pyrazine-2-carboxylic acidethyl ester

Intermediate B1: Carbamimidoyl-nitroso-acetic acid ethyl ester

To a solution of 2M ammonia in Ethanol (152 ml, 0.304 mmol) at 0° C. to5° C., ethyl ethoxycarbonylacetimidate HCl (25 g, 0.127 mmol) was addedover 30 minutes. The reaction was stirred vigorously at this temperaturefor 3 hours, after which a solution of sodium nitrite in water (9.63 g,0.139 mmol) was added in a single portion. The pH of the mixture wasadjusted to pH6 with the addition of 5N HCl. The reaction mixture wasleft to stir at RT overnight. The yellow precipitate formed was filteredunder vacuum, washed with water and dried to give the title compound;

¹H NMR (400 MHz, DMSO-d6) δ 10.1 (2H, br s), 7.6 (2H, br s), 4.3 (2H,q), 1.3 (3H, t).

Intermediate B2: Amino-carbamimidoyl-acetic acid ethyl ester

To a solution of carbamimidoyl-nitroso-acetic acid ethyl ester (5.5 g,31.4 mmol) in ethanol/5M HCl (1:1 ratio, 250 ml) was added 10% Pd/C (1.3g). The reaction mixture was hydrogenated (H_(2(g))) at low pressureover 2 nights. The Pd/C was filtered through Celite® (filter material)and the filtrate reduced in vacuo to give the title compound as a whitesolid. This was taken through to the next step as crude.

Intermediate B: 3-Amino-5-trifluoromethyl-pyrazine-2-carboxylic acidethyl ester

To a mixture of amino-carbamimidoyl-acetic acid ethyl ester (2 g, 9.22mmol) and water (50 ml), a 20% aqueous solution of trifluoropyruvicaldehyde (2.32 g, 18.43 mmol) was added. To this mixture, sodium acetate(5.29 g, 64.52 mmol) was added (pH of the reaction mixture was pH5). Thereaction mixture was left to stir at RT overnight. The resultantprecipitate was filtered under vacuum purification by chromatography onsilica eluting with iso-hexane: EtOAc (gradient of 0 to 10% EtOAc)afforded the title compound

¹H NMR (400 MHz, DMSO-d6) δ 8.4 (1H, s), 7.8 (2H, br s), 4.4 (2H, q),1.4 (3H, t).

Intermediate BA 3-Amino-5,6-bis(trifluoromethyl)pyrazine-2-carboxylicacid

Step 1: Ethyl 3-amino-5,6-bis(trifluoromethyl)pyrazine-2-carboxylate

The title compound was prepared from amino-carbamimidoyl-acetic acidethyl ester (Intermediate B2) and 1,1,1,4,4,4-hexafluorobutane-2,3-dioneanalogously to Intermediate B; 10 LCMS Rt=4.72 minutes, [M+H]+304.2/326.1 Method 10 minLC_v002.

Step 2: 3-Amino-5,6-bis(trifluoromethyl)pyrazine-2-carboxylic acid

To a stirring solution of ethyl3-amino-5,6-bis(trifluoromethyl)pyrazine-2-carboxylate (300 mg, 0.990mmol) in EtOH (10 ml), 2M NaOH (0.495 ml, 0.990 mmol) was added dropwiseover 1 minute. After stirring at RT for 30 minutes the reaction mixturewas poured into water (30 ml) and the pH was adjusted to pH 4 byaddition of 1M HCl. The mixture was extracted with EtOAc (2×50 ml) andthe combined organic extracts were washed with brine (30 ml), dried overMgSO₄ (5 g), filtered and concentrated in vacuo to afford the titlecompound as an off white crystalline solid;

¹H NMR (400 MHz, DMSO-d6) δ 8.6-9.2 (2H, broad hump), 7.8-8.3 (2H, broadhump), 4.4 (2H, q), 1.32 (3H, t).

Intermediate C 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylicacid

Intermediate C1: 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylicacid ethyl ester

To a solution of 3-amino-5-trifluoromethyl-pyrazine-2-carboxylic acidethyl ester (Intermediate B) (30 mg, 0.13 mmol) in acetic acid (5 ml),sodium carbonate (15 mg, 0.14 mmol) was added. To this mixture, half thecontents of a solution of bromine (7 μL, 0.13 mmol) in acetic acid (5ml) were added, followed by the addition of sodium carbonate ((15 mg,0.14 mmol). The remaining solution of bromine in acetic acid was addedand the reaction mixture was left to stir at RT for 2 hours. The mixturewas diluted with water and the resulting yellow precipitate was filteredunder vacuum to afford the title compound.

Intermediate C: 3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylicacid

To a stirring solution of3-amino-5-trifluoromethyl-pyrazine-2-carboxylic acid ethyl ester (10 g,31.8 mmol) in ethanol (20 ml), 2M NaOH (20 ml, 31.8 mmol) was added. Theresulting solution was stirred at RT for 5 minutes and poured into water(50 ml). The pH was adjusted to pH6 with the addition of 1M HCl. Theresulting suspension was filtered under vacuum, washed with water (20ml) and dried to afford the title compound; MS m/z 287 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d6) δ 7.98 (2H, s).

Intermediate D 3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylicacid

Intermediate D1:6-Bromo-3-(2,5-dimethyl-pyrrol-1-yl)-5-trifluoromethyl-pyridine-2-carboxylicacid methyl ester

3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methylester (Intermediate A4) (2 g, 6.69 mmol) was suspended in toluene (8ml), and treated with p-toluenesulfonic acid (TsOH) (0.115 g, 0.669mmol) and acetonylacetone (0.941 ml, 8.03 mmol). The reaction mixturewas heated at reflux for 2 hours (using Dean-Stark apparatus) andallowed to cool to RT overnight. The resulting dark red/black solutionwas concentrated in vacuo to remove toluene and the crude residuediluted with EtOAc (200 ml), washed with NaHCO₃ (50 ml), dried (MgSO₄)and concentrated in vacuo to give a brown solid. Purification of thesolid by chromatography on silica eluting with EtOAc/iso-hexane affordedthe title compound; LC-MS Rt=5.58 min [M+H]+ 377/379 (Method 10minLC_v002).

1H NMR (400 MHz, DMSO-d6) δ 8.50 (1H, s), 7.77 (2H, s), 5.83 (3H, s),1.90 (6H, s); 19F NMR (400 MHz, DMSO-d6) δ −62.26 (CF3, s).

Intermediate D2:3-(2,5-Dimethyl-pyrrol-1-yl)-6-methoxy-5-trifluoromethyl-pyridine-2

6-Bromo-3-(2,5-dimethyl-pyrrol-1-yl)-5-trifluoromethyl-pyridine-2-carboxylicacid methyl ester (2 g, 5.30 mmol) was dissolved in MeOH (40 ml) andtreated with 2M NaOH (20 ml) to give a suspension which was stirred atRT for 1 h to afford a clear solution. The solvent was removed in vacuoand the resulting residue was acidified to pH1 with 5M HCl. The mixturewas extracted with EtOAc (200 ml) and the organic extract was dried(MgSO₄) and concentrated in vacuo to afford the title compound as a darkbrown solid which was used in the next step without furtherpurification; LC-MS Rt=1.50 min [M+H]+ 315.2.1/316.2 (Method 2minLC_v002); 1H NMR (400 MHz, DMSO-d6) δ14.42-12.61 (COOH, b), 8.25 (1H,s), 5.84 (2H, s), 4.13 (3H, s), 1.97 (6H, s); 19F NMR (400 MHz, DMSO-d6)δ −62.43 (CF3, s).

Intermediate D:3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid

3-(2,5-Dimethyl-pyrrol-1-yl)-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylicacid (2.1 g, 6.68 mmol) was dissolved in EtOH (40 ml) and water (20 ml).To this mixture was added TEA (2.79 ml, 20.05 mmol) followed byhydroxylamine hydrochloride (4.64 g, 66.8 mmol). The resulting mixturewas heated at reflux for 5 hours. After cooling to RT, the mixture wasdiluted with EtOAc (100 ml) and washed with aqueous HCl (1M, 100 ml).The aqueous phase was back extracted with EtOAc (100 ml) and thecombined organic phases washed with brine (100 ml), dried (MgSO4) andconcentrated in vacuo to afford the product as an orange solid. Thematerial can be used crude or recrystallised from isohexane-EtOAc (10:1)LC-MS Rt=1.0 min [M+H]+ 237 (Method 2 minLC_v003)

1H NMR (400 MHz, DMSO-d6) δ 8.5 (NH2, b), 7.70 (1H, s), 3.89 (3H, s).

Intermediate DA3-(2,5-Dimethyl-1H-pyrrol-1-yl)-6-(pyrrolidin-1-yl)-5-(trifluoromethyl)picolinicacid

Step 1:6-Bromo-3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-(trifluoromethyl)picolinicacid

6-Bromo-3-(2,5-dimethyl-pyrrol-1-yl)-5-trifluoromethyl-pyridine-2-carboxylicacid methyl ester (1.9 g, 5.04 mmol) and 2M NaOH (2.52 ml, 5.04 mmol) inTHF (10 ml) was stirred at RT for 1 hour. The reaction mixture waspoured into water (50 ml) and the pH was adjusted to pH 4 by addition of1M HCl. The mixture was extracted with EtOAc (2×50 ml) and the organicportion was washed with brine (30 ml), dried over MgSO₄ (5 g), filteredand concentrated to give the title compound as a crystalline orangesolid; LC_MS Rt=1.21 min [M+H]+ 363.1 (Method 2 minLC_v003).

Step 2:3-(2,5-Dimethyl-1H-pyrrol-1-yl)-6-(pyrrolidin-1-yl)-5-(trifluoromethyl)picolinicacid

To a stirring solution of6-bromo-3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-(trifluoromethyl) picolinicacid (300 mg, 0.826 mmol) in THF (1 ml), pyrrolidine (0.136 ml, 1.652mmol) was added. The orange solution was stirred at RT overnight. Thereaction mixture was partitioned between 0.5M HCl (30 ml) and EtOAc (30ml) and shaken. The organic portion was separated and washed with brine(30 ml), dried over MgSO₄, filtered and concentrated in vacuo to give ared oil. The crude product was purified on silica eluting with 0-40%EtOAc in iso-hexane to afford the title product;

1H NMR (400 MHz, DMSO d6) δ 13.45 (1H, br s), 7.88 (1H, s), 5.74 (2H,s), 3.58 (5H, br s), 1.88-2.0 (11H, unresolved peaks).

Intermediate DB3-(2,5-Dimethyl-1H-pyrrol-1-yl)-6-ethoxy-5-(trifluoromethyl)picolinicacid

Step 1: Methyl3-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methoxy-5-(trifluoromethyl)picolinate

3-(2,5-Dimethyl-pyrrol-1-yl)-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylicacid (Intermediate D2)(500 mg, 1.591 mmol) in methanol (15.91 ml) wastreated with H₂SO₄ (0.0424 ml, 0.795 mmol) and the solution was heatedat reflux for overnight. The solvent removed was removed in vacuo andthe resulting brown oil was neutralised to pH 7 using saturated sodiumbicarbonate. The mixture was extracted with EtOAc (20 ml) and thecombined organic extracts were washed with water (20 ml), brine (20 ml),passed though a phase separator and concentrated in vacuo. Purificationof the crude product by chromatography on silica eluting withiso-hexane: EtOAc (gradient of 0 to 10% EtOAc) afforded the titlecompound as an off-white powder.

1H NMR (400 MHz, DMSO-d6) δ 8.3 (1H, s), 5.8 (2H, s), 4.1 (3H, s), 3.6(3H, s), 1.9 (6H, s).

Step 2: Methyl3-(2,5-dimethyl-1H-pyrrol-1-yl)-6-hydroxy-5-(trifluoromethyl)picolinate

Methyl3-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methoxy-5-(trifluoromethyl)picolinate(100 mg, 0.305 mmol) in acetonitrile (3.05 ml) was treated with KI (202mg, 1.218 mmol) and TMS-Chloride (0.156 ml, 1.221 mmol) and heated atreflux for 6 hours. The solvent removed was in vacuo and the crudeproduct was dissolved in EtOAc (20 ml) and washed with water (2×10 ml)and brine (10 ml), dried over a phase separator and concentrated invacuo. Purification of the crude product by chromatography on silicaeluting with iso-hexane: EtOAc (gradient of 0 to 30% EtOAc) afforded thetitle compound as an yellow powder. LC-MS Rt=1.11 mins [M+H]+ 315.4(Method 2 minLC_v003).

Step 3: Methyl3-(2,5-dimethyl-1H-pyrrol-1-yl)-6-ethoxy-5-(trifluoromethyl)picolinate

Methyl3-(2,5-dimethyl-1H-pyrrol-1-yl)-6-hydroxy-5-(trifluoromethyl)picolinate(62 mg, 0.168 mmol) in 1,4-dioxane (1.5 ml) (dry) was treated with EtOH(0.020 ml, 0.335 mmol) and triphenylphosphine (88 mg, 0.335 mmol) andthe solution stirred. DEAD (0.053 ml, 0.335 mmol) was added dropwise andthe reaction mixture stirred at room temperature for 2 hours. Thesolvent was removed in vacuo and purification of the crude product bychromatography on silica eluting with iso-hexane: EtOAc (gradient of 0to 10% EtOAc) afforded the title compound;

1H NMR (400 MHz, DMSO-d6) δ 8.3 (1H, s), 5.8 (2H, s), 4.5 (2H, q), 3.6(3H, s), 1.9 (6H, s), 1.4 (3H, t).

Step 4:3-(2,5-Dimethyl-1H-pyrrol-1-yl)-6-ethoxy-5-(trifluoromethyl)picolinicacid

Methyl3-(2,5-dimethyl-1H-pyrrol-1-yl)-6-ethoxy-5-(trifluoromethyl)picolinate(140 mg, 0.409 mmol) was dissolved in THF (2.045 ml). NaOH (0.613 ml,1.226 mmol) was added and heated at reflux for 6 hours. The solvent wasremoved in vacuo and the resulting mixture was diluted with EtOAc (25ml) was acidified to pH 1 using HCl (5M). The organic portion washedwith brine, dried using a phase separator and concentrated in vacuo toafford the title compound as a yellow oil.

LC-MS Rt=1.26 mins [M+H]+ 329.2 Method 2 minLC_v003.

Intermediate E 3-Amino-5-trifluoromethyl-pyridine-2-carboxylic acid

To a stirring solution of3-Amino-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester(Intermediate A3) (1 g, 4.54 mmol) in MeOH (20 ml) was added 2M NaOH(0.182 g, 4.54 mmol). The orange solution was stirred at RT for 1 minuteand then into water (10 ml). The solution was acidified to pH1 with theaddition of 1M HCl and the product was extracted with EtOAc (150 ml).The organic portions were combined, washed with brine (50 ml), driedover MgSO₄ and concentrated in vacuo to afford the title compound as anorange solid; LC-MS Rt=0.82 mins [M+H]+ 207.1 (Method 2 minLC_v002); 1HNMR (400 MHz, DMSO-d6) δ 13.9 (1H, broad hump), 8.11 (1H, s), 7.59 (1H,s), 7.08 (2H, broad hump) (trace of EtOAc present but correlates toproposed structure).

Intermediate G3-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid

A mixture comprising3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid(Intermediate A) (1 g, 3.51 mmol), 4-fluorophenylboronic acid (0.736 g,5.26 mmol) and 1,1′Bis(diphenylphosphoshio)ferrocene palladiumdichloride (0.286 g, 0.351 mmol) and 1.0M Cs₂CO₃ (3.3 ml) in THF (10 ml)was heated to reflux for 10 hours. After cooling to RT, the mixture waspartitioned between DCM (100 ml) and 1 M NaOH (2×100 ml). The aqueousphase was acidified with 5M HCl and the resulting milky solution wasextracted into DCM (2×100 ml). The organic portion was separated, dried(MgSO₄) and concentrated in vacuo to afford the product as a crude oil.The crude material was purified by flash chromatography on silicacartridge eluting with a gradient of DCM: MeOH from 0% to 10% MeOH toafford the title product as a pale yellow solid;

1H NMR (DMSO-d6, 400 MHz) δ 12.9 (1H, br s, COOH), 7.7 (1H, s, CH,Ar—H), 7.4 (2H, m, Ar—H), 7.25 (2H, m, Ar—H), 7.1 (2H, br s, NH2).

Intermediate GA 3-Amino-6-cyclopropyl-5-(trifluoromethyl)picolinic acid

Step 1: 3-Amino-6-cyclopropyl-5-(trifluoromethyl)picolinic acid

A microwave vial was charged withamino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester(Intermediate A4) (0.5 g, 1.754 mmol), cyclopropylboronic acid (0.753 g,8.77 mmol), and 1,1′Bis(diphenylphosphosphino) ferrocene palladiumdichloride (0.143 g, 0.175 mmol). The mixture was taken up as a solutionin THF (6 ml) and flushed with N₂, sealed and heated using microwaveradiation at 150° C. for 20 minutes. The reaction mixture was filteredthrough Celite® (filter material) and washed through with EtOAc (20 ml).The filtrate was partitioned between EtOAc (30 ml) and water (50 ml).The phases were separated and the organic portion was washed with brine(30 ml), dried over MgSO₄, filtered and concentrated under vacuum. Thecrude material was taken up in EtOAc (20 ml) and dry loaded onto silica(2-3 g). Material then purified on the Combiflash Rf Teledyne ISCOSystem 100% Isohexane to 60% EtOAc:Isohexane to afford semi purematerial which was used without further purification.

Step 2: 3-Amino-6-cyclopropyl-5-(trifluoromethyl)picolinic acid

To a stirring solution of3-amino-6-cyclopropyl-5-(trifluoromethyl)picolinic acid (472 mg, 1.814mmol) in THF (10 ml), 2M NaOH (10 ml, 20.00 mmol) was added. The orangesolution was stirred at RT for 2 days. The reaction mixture was pouredinto water (30 ml) and the pH adjusted to pH6 with the addition of 1MHCl. The product was extracted with EtOAc (50 ml) and the organicportion was dried over MgSO₄, filtered and concentrated in vacuo to givethe title compound as a red/orange oil. LC-MS Rt=1.10 mins [M+H]+ 247.1(Method 2 minLC_v003);

Intermediate H3-Amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylicacid

Intermediate H1:3-Amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylicacid methyl ester

3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methylester (Intermediate A4) (3 g, 10.03 mmol), 2,4-dichlorophenylboronicacid (2.297 g, 12.04 mmol), potassium phosphate (4.26 g, 20.06 mmol) andFibrecat® 1034A (Johnson Matthey, polymer supported palladium complex)(500 mg, 10.03 mmol) were suspended in toluene (50 ml) and water (15ml). The reaction mixture was heated to 110° C. under vigorous stirringfor 3 hours. The mixture was allowed to cool to RT and EtOAc (100 ml)was added. The organic layer was separated and washed with brine (15ml). MP-TMT (macroporous polystyrene-bound trimercaptotriazine, 3 g,Polymern labs) was added and stirred for 1 hour at RT. MgSO₄ was addedand the suspension filtered off. The filtrate was concentrated in vacuoand purification of the residue by reverse phase chromatography (130 gC18 column) eluting with water/MeOH afforded the title compound as awhite solid; LS-MS Rt=1.55 mins [M+H]+ 365 (Method 2 minLC_v002).

Intermediate H:3-Amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylicacid

3-Amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylicacid methyl ester (0.9 g, 2.465 mmol) was suspended in MeOH (15 ml) andNaOH 2M (2.465 ml, 4.93 mmol) was added under stirring. 1,4-Dioxane(15.00 ml) was added and the solution was left standing at RT overnight. The solvent was removed in vacuo and the resulting residue wasdissolved in water (10 ml) and carefully acidified to pH4 with slowaddition of 2M HCl (2 ml) whilst stirring. The mixture was extractedwith EtOAc (20 ml) and the organic portion was washed with brine andconcentrated in vacuo. The residue was purified by reverse phasechromatography (130 g C18 column) eluting with water/MeOH to afford thetitle compound; LS-MS Rt=1.57 mins [M+H]+ 351.0 (Method 2 min LC_v002).

Intermediate I3-Amino-6-(4-chloro-2-methyl-phenyl)-5-trifluoromethyl-pyridine-2-carboxylicacid

This compound was prepared from3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methylester (Intermediate A4) and 4-chloro-2-methylphenylboronic acidanalogously to Intermediate H; LC-MS Rt=1.53 mins, [M+H]+ 331 (Method 2min LC_v002).

Intermediate J 2-Aminomethyl-1,1,1,3,3,3-hexafluoro-propan-2-ol

To a stirred mixture of 35% ammonium solution (1 ml) and diethyl ether(1 ml) was added 3,3,3-trifluoro-2-(trifluoromethyl)-1,2-propenoxide(500 mg, 2.78 mmol) dropwise and the reaction mixture was left to stirat RT for 3 hours. The reaction mixture was separated and the aqueouslayer was extracted with diethyl ether (2×3 ml). The combined organicportions were dried (MgSO₄) and concentrated in vacuo to give a whitecrystalline solid; 1H NMR (400 MHz, DMSO-d6) δ 4.20 (broad), 3.30(broad), 3.15 (s), 3.02 (s), 2.50 (s, DMSO). ¹⁹F NMR (400 MHz, DMSO-d6)δ −85 (CF3), −84.5 (CF3).

Intermediate K5-Amino-6′-methyl-3-(trifluoromethyl)-2,3′-bipyridine-6-carboxylic acid

Intermediate K1:5-Amino-6′-methyl-3-trifluoromethyl-[2,3′]bipyridinyl-6-carboxylic acidmethyl ester

This compound was prepared from3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methylester (Intermediate A4) and 2-methylpyridine-5-boronic acid analogouslyto 3-amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylicacid (Intermediate G); LC-MS Rt 0.96 min [M+H]+ 312 (Method 2minLC_v002); 1H NMR (400 MHz, DMSO-d6) δ 8.41 (1H, s), 7.79 (1H, s),7.69 (1H, dd), 7.32 (1H, d), 7.10 (2H, s), 3.82 (3H, s), 2.52 (3H, s).

Intermediate K:5-Amino-6′-methyl-3-(trifluoromethyl)-2,3′-bipyridine-6-carboxylic acid

This compound was prepared from:5-Amino-6′-methyl-3-trifluoromethyl-[2,3′]bipyridinyl-6-carboxylic acidmethyl ester analogously to3-amino-6-(4-chloro-2-methyl-phenyl)-5-trifluoromethyl-pyridine-2-carboxylicacid methyl ester (Intermediate I); LC-MS Rt 0.90 min; [M+H]+ 298(Method 2 minLC_v002); 1H NMR (400 MHz, DMSO-d6) δ 12.90 (1H, broad),8.45 (1H, s), 7.72 (2H), 7.32 (1H, d), 7.12 (2H, broad), 2.51 (3H).

Intermediate KA 5-Amino-3-(trifluoromethyl)-2,4′-bipyridine-6-carboxylicacid

The title compound was prepared analogously to Intermediate K using theappropriate boronic acid in step 1; 1H NMR (400 MHz, DMSO-d6) δ 13.00(1H, broad), 8.65 (2H, d), 7.65 (1H, s), 7.43 (2H, d), 7.18 (2H, broad).

Intermediate M3-(2,5-Dimethyl-pyrrol-1-yl)-5,6-bis-trifluoromethyl-pyridine-2-carboxylicacid

Intermediate M1:3-(2,5-Dimethyl-pyrrol-1-yl)-5,6-bis-trifluoromethyl-pyridine-2-carboxylicacid methyl ester

A stirred mixture of KF (2.12 g, 5.62 mmol) and CuI (0.490 g, 8.43 mmol)was heated in a sealed 10.0-20.0 ml microwave vial under vacuum until aslight greenish colour began to appear. The vial was then placed undernitrogen to cool. A solution6-bromo-3-(2,5-dimethyl-pyrrol-1-yl)-5-trifluoromethyl-pyridine-2-carboxylicacid methyl ester (Intermediate D) (2.64 ml, 16.86 mmol) in 1:1 dryDMF/dry NMP (14 ml) was then added, followed by TMS-CF₃ (2.64 ml, 16.86mmol). A new septum was then used to seal the vial and the reactionmixture was heated using microwave radiation with stirring at 100° C.for 3 h and allowed to cool. The mixture was added to 5M NH3 solution(50 ml) and then extracted with diethyl ether (4×50 ml). The combinedorganic extracts were washed with 5M NH₃ solution (3×20 ml), 1M HCl (50ml), sat. sodium bicarbonate solution (2×50 ml), brine (50 ml), dried(MgSO₄) and concentrated in vacuo to give a brown oil. The crudematerial was purified by chromatography on silica eluting withIso-hexane/EtOAc, 0-10% to afford the title compound as an orange solid;LC-MS Rt 1.37 min; MS m/z 367.1 [M+H]+; Method 2 minLC_v003.

Intermediate M:3-(2,5-Dimethyl-pyrrol-1-yl)-5,6-bis-trifluoromethyl-pyridine-2-carboxylicacid

To a stirred solution3-(2,5-dimethyl-pyrrol-1-yl)-5,6-bis-trifluoromethyl-pyridine-2-carboxylicacid methyl ester (1.28 g, 3.49 mmol) in methanol (25 ml) was added 1MNaOH (7 ml, 6.99 mmol) and the reaction mixture was left to stir at RTfor 30 min. The solvent was removed in vacuo and water (20 ml) was addedto the remaining residue. The pH was adjusted to pH 4/5 by the additionof 1M HCl. The mixture was extracted with EtOAc (3×20 ml) and thecombined organic extracts were washed with brine (30 ml), dried (MgSO₄)and concentrated in vacuo and dried in a vacuum oven (50° C.) overnightto give the crude title product as an orange solid which was usedwithout further purification; LC-MS: Rt 1.23 min; MS m/z 353.1 [M+H]+;Method 2 minLC_v003.

Intermediate N3,3,3-Trifluoro-N2-(4-methoxybenzyl)-2-methylpropane-1,2-diamine

Step 1:1-(4-methoxyphenyl)-N-(1,1,1-trifluoropropan-2-ylidene)methanamine

To a stirring solution of trifluoroacetone (7.75 g, 69.2 mmol) indiethyl ether (60 ml) at −40° C. was added 4-methoxybenzyl amine (9.49g, 69.2 mmol) and triethylamine (14 g, 138 mmol) in diethyl ether (40ml). A cooled (0° C.) mixture of TiCl₄ (6.56 g, 34.6 mmol) in hexane (40ml) at was added dropwise over 10 minutes and the resulting mixture wasallowed to warm up to ambient temperature over 20 mins and stirred at50° C. for 2.5 h. The inorganic precipitate was removed by filtrationand washed with diethyl ether. The filtrate was concentrated in vacuo toafford a yellow oil. Purification of the crude product by chromatographyon silica eluting with 0% to 25% EtOAc in iso-hexane afforded the titleproduct.

Step 2: 3,3,3-trifluoro-2-(4-methoxybenzylamino)-2-methyl propanenitrile

To a cooled (0° C.) solution of1-(4-methoxyphenyl)-N-(1,1,1-trifluoropropan-2-ylidene)methanamine (4.41g, 19.07 mmol) in DCM (100 ml) was added cyanotrimethylsilane (2.84 g,28.6 mmol) and magnesium bromide. The mixture was stirred at RT for 90 hand then diluted with sat. NaHCO₃ (200 ml). After stirring at RT for 1h, the organic phase was separated, washed with a further portion ofsat. NaHCO₃ (100 ml), dried over MgSO₄ and concentrated in vacuo toafford the title compound.

Step 3: 3,3,3-trifluoro-N2-(4-methoxybenzyl)-2-methylpropane-1,2-diamine

To a cooled (0° C.) solution of3,3,3-trifluoro-2-(4-methoxybenzylamino)-2-methyl propanenitrile (1.5 g,5.81 mmol) in dry diether ether (50 ml) was added LiAlH4 (11.62 ml of a2M solution in THF) and the resulting mixture was stirred at RTovernight. The reaction mixture was hydrolyzed by successive addition ofwater 15% KOH, and water. The resulting precipitate was filtered onCelite® (filter material) and the organic portion was washed with water,dried over MgSO₄ and concentrated under reduced pressure to afford thetitle product; 1H NMR (400 MHz, Methanol-d4) δ 7.97 (1H, s), 7.85 (1H,s), 7.60 (1H, s), 3.97 (3H, s), 3.77 (1H, m), 3.56 (1H, m), 1.37 (3H, s)

LC-MS: Rt 3.22 min; MS m/z 412.3 [M+H]+; Method 10 minLC_v003.

Intermediate O Benzo[d]isoxazol-3-ylmethanamine

The title compound was prepared according to the procedure of Pigini,Maria; Giannella, Mario; Gualtieri, Fulvio; Melchiorre, Carlo; Bolle,Paola; Angelucci, Luciano. Analogs with a 1,2-benzisoxazole nucleus ofbiologically active indole derivatives. Ill. Tryptamine and gramineisosteres. European Journal of Medicinal Chemistry (1975), 10(1), 29-32(Compound 11 page 31-32).

Intermediate P Methyl3-amino-6-(oxazol-2-yl)-5-(trifluoromethyl)picolinate

A solution of 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylicacid methyl ester (Intermediate A4) (500 mg, 1.672 mmol),2-(tributylstannyl)oxazole (0.704 ml, 3.34 mmol) andtetrakis(triphenylphosphine)palladium(0) (193 mg, 0.167 mmol) in dioxane(10 ml) was heated at reflux for 13 hours. After cooling to roomtemperature over 8 hours, the solvent was evaporated and the resultingresidue triturated with hot methanol to remove a yellow solid impurity.The remaining crude material was used without further purification.LC-MS: Rt 0.95 min; MS m/z 288 [M+H]+; Method 2 minLC_v003.

Intermediate PA3-Amino-6-furan-2-yl-5-trifluoromethyl-pyrazine-2-carboxylic acid

Step 1: 3-Amino-6-furan-2-yl-5-trifluoromethyl-pyrazine-2-carboxylicacid

The title compound was prepared from3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid ethyl ester(Intermediate C1) and tributyltin-2-furylstannane analogously to methyl3-amino-6-(oxazol-2-yl)-5-(trifluoromethyl)picolinate (Intermediate P)

Step 2: 3-Amino-6-furan-2-yl-5-trifluoromethyl-pyrazine-2-carboxylicacid

The title compound was prepared from3-amino-6-furan-2-yl-5-trifluoromethyl-pyrazine-2-carboxylic acid and 6MNaOH analogously to3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid(Intermediate C, final step).

Intermediate Q 2-Hydroxy-3-methyl-2-(trifluoromethyl)butan-1-aminiumchloride

Step 1: 1,1,1-Trifluoro-3-methyl-2-(nitromethyl)butan-2-ol

A cooled (0° C.) solution of lithium hydroxide (0.048 g, 2.015 mmol) inwater (20 ml) was stirred and treated with nitromethane (1.23 g, 20.15mmol), 1,1,1-trifluoro-3-methylbutan-2-one (3.11 g, 22.17 mmol),cetyltrimethylammonium Chloride (0.871 g, 2.72 mmol) and MgSO₄ (0.485 g,4.03 mmol). The white suspension was stirred at 0° C. for 1 hr, then atRT for 2 days. The resulting biphasic mixture was separated and the moredense lower layer was collected and dissolved in diethyl ether (30 ml).The mixture was dried over MgSO₄, filtered and concentrated in vacuo togive a pale yellow oil. The oil was taken up in diethyl ether (10 ml)and passed through a pre-packed SCX-2 cartridge eluting with 100%diethyl ether. The filtrate was concentrated in vacuo to afford thetitle compound as a colourless oil. ¹H NMR (400 MHz, CDCl₃): δ 4.74 (1H,d), 4.59 (1H, d), 4.29 (1H, s), 2.29 (1H, m), 1.1 (6H, two sets ofunresolved doublets)

Step 2: 2-Hydroxy-3-methyl-2-(trifluoromethyl)butan-1-aminium chloride

To a solution of 1,1,1-trifluoro-3-methyl-2-(nitromethyl)butan-2-ol (753mg, 3.74 mmol) in EtOH (10 ml) in a 25 ml medium pressure glasshydrogenation vessel under N₂, 10% Pd on carbon (39.8 mg, 0.374 mmol)was added. The vessel was flushed with N₂, followed by H₂ (22.64 mg,11.23 mmol) at 5 bar pressure and stirred at RT for 6 days. The mixturewas filtered through Celite® and washed through with EtOH (30 ml),followed by DCM (10 ml). The filtrate was concentrated under vacuum togive a colourless oil. The crude product was taken up in methanol (20ml) and treated with a 1.25M HCl in methanol solution. The resultingcolourless solution was stirred at RT for 1 hour and concentrated undervacuum to afford the title compound;

1H NMR (400 MHz, DMSO-d6) δ 8.04 (3H, broad peak), 6.74 (1H, s), 3.58(broad peak), 3.6 (2H, m), 2.12 (1H, m), 0.99 (6H).

Intermediate R 3-Amino-1,1,1-trifluoro-2-methylpropan-2-ol hydrochloride

Step 1: 1,1,1-trifluoro-2-methyl-3-nitropropan-2-ol

To LiOH (0.193 g, 8.06 mmol) in a 3-neck roundbottom flask was addedwater (25 ml), nitromethane (3.76 ml, 81 mmol) and trifluoroacetone(7.95 ml, 89 mmol). Cetyltrimethylammonium chloride (3.8 g, 10.88 mmol)and MgSO₄ (1.9 g, 16.12 mmol) were added and the resulting yellowsolution stirred at 20-25° C. for 2 days. The reaction mixture waspoured into diethyl ether (120 ml) and washed with water (3×200 ml) andbrine (1×100 ml). The organic portion was dried over MgSO₄ andconcentrated in vacuo to afford the title compound as a yellow liquid.1H NMR (CDCl₃, 400 MHz): δ 4.7 (1H d), δ 4.5 (1H, d), δ 3.7 (1H, broad),δ 1.6 (3H, s).

Step 2: 3-Amino-1,1,1-trifluoro-2-methylpropan-2-ol hydrochloride

Pd/C was added (1 g) to a 200 ml glass vessel. Ethanol (50 ml, dry) wasadded cautiously under an atmosphere of CO₂.1,1,1-Trifluoro-2-methyl-3-nitropropan-2-ol (10 g, 57.8 mmol) wasdissolved in ethanol (50 ml, dry) and added to the glass vessel. Thereaction mixture was put under a positive pressure of hydrogen (5 bar)at room temperature and hydrogenated for 2 days. The reaction mixturewas filtered through Celite® (filter material) and washed with excessethanol. The solvent was removed in vacuo to yield a colourless oil. Theoil was dissolved in MeOH (50 ml) and treated dropwise with HCl (1M) inMeOH (30 ml). The solution was left to stir for 30 minutes andconcentrated in vacuo azeotroping with MeCN to afford the title compoundas a waxy white solid; 1H NMR (DMSO-d6, 400 MHz) δ 8.3 (3H, broad s),6.9 (1H, broad), 3.0 (2H, q), 1.4 (3H, s).

Intermediate RA (S)-3-Amino-1,1,1-trifluoro-2-methylpropan-2-olhydrochloride

Step 1: Benzyl 3,3,3-trifluoro-2-hydroxy-2-methylpropylcarbamate

To a stirring suspension of amino-1,1,1-trifluoro-2-methylpropan-2-olhydrochloride (Intermediate R) (1.5 g, 8.35 mmol) in DCM (50 ml) wasadded TEA 93.54 g, 35.0 mmol) followed by benzyl2,5-dioxopyrrolidin-1-yl carbonate (1.983 g, 7.96 mmol). The mixture wasstirred at RT for 6 hours and then diluted with water. The organicportion was separated using a phase separator and concentrated in vacuo.Purification by chromatography on silica eluting with 0-70% EtOAc iniso-hexane afforded the title product; 1H NMR (400 MHz, DMSO-d6) δ 7.34(6H, m), 5.98 (1H, s), 5.05 (2H, s), 3.31 (1H, m), 3.18 (1H, m), 1.21(3H, s) LC-MS: Rt 1.05 min; MS m/z 278.1 [M+H]+; Method 2 minLC_v003.

Step 2: Separation of Enantiomers of benzyl3,3,3-trifluoro-2-hydroxy-2-methyl propylcarbamate

Benzyl 3,3,3-trifluoro-2-hydroxy-2-methylpropylcarbamate (1.7 g) wasdissolved in 2-propanol (10 ml) and purified using the followingchromatographic conditions:

Mobile Phase: 10% 2-propanol/90% CO₂

Column: 2× Chiralcel OJ-H, 250×10 mm id, 5 μm (columns coupled inseries)

Detection: UV@ 220 nm

Flow rate: 10 ml/min

Sample concentration: 1.7 g in 10 ml 2-propanol

Injection volume: 75 μl

First Eluted Peak:

Rt=6.94 minutes (R)-benzyl 3,3,3-trifluoro-2-hydroxy-2-methylpropylcarbamate

Second Eluted Peak:

Rt=8.04 minutes (S)-benzyl 3,3,3-trifluoro-2-hydroxy-2-methylpropylcarbamate (Stereochemistry confirmed by analysis of final compoundprepared by subsequent steps)

Step 3: (S)-3-Amino-1,1,1-trifluoro-2-methylpropan-2-ol hydrochloride

A mixture comprising (S)-benzyl 3,3,3-trifluoro-2-hydroxy-2-methylpropylcarbamate in EtOH (165 ml) was pumped through a H-Cube(hydrogenation reactor, 1-2 ml/min, 1 bar pressure, RT) for 8 hoursusing a 10% palladium on carbon catalyst cartridge. 1.25 M HCl inmethanol (130 ml) was added to the mixture was stirred for 30 mins. Thesolvent was removed in vacuo azeotroping with MeCN to afford the titleproduct as a white powder; 1H NMR (400 MHz, DMSO-d6) δ 8.3 (3H, broad),6.8 (1H, s), 3.0 (2H, s), 1.5 (3H, s).

Alternatively, racemic 3-Amino-1,1,1-trifluoro-2-methylpropan-2-ol canbe resolved into separate enantiomers by recrystallistion with either(S)-Mandelic acid or L-tartaric acid in isopropanol or ethanol.

Intermediate S 2-Aminomethyl-1,1,1,3,3,3-hexafluoro-propan-2-ol

3,3,3-Trifluoro-2-(trifluoromethyl)-1,2-propenoxide (1 g, 5.55 mmol) wasadded to a stirred solution of aqueous ammonia solution (0.88 g/ml, 3ml) and diethyl ether (3 ml). The resulting colourless solution wasstirred at room temperature for 3 hours. The biphasic mixture wasseparated and the aqueous portion was further extracted with diethylether (2×5 ml). The combined organic layers were dried over MgSO₄ andconcentrated in vacuo (no heating) to afford the title compound as awhite crystalline solid which was used without further purification; 1HNMR (400 MHz, DMSO-d6) signals unassigned δ 4.20 (broad), 3.15 (s).

Intermediate T 3,3,3-Trifluoro-2-methoxy-2-methylpropan-1-amine

Step 1:2-(3,3,3-Trifluoro-2-hydroxy-2-methylpropyl)isoindoline-1,3-dione

A mixture comprising 3,3,3-trifluoro-2-hydroxy-2-methyl-propyl-ammonium(0.9 g), phthalic anhydride (1.039 g) and DIPEA (2.188 ml) in chloroform(30 ml) was heated at 70° C. for 5 hours. After cooling to RT, themixture was washed with water and passed through a phase separator. Theorganic phase was reduced to dryness. The crude product was purified bychromatography on silica, eluting in a 0% to 30% iso-hexane:EtOAcremoved to give the title product; 1H NMR (400 MHz, Methanol-d4) δ 7.92(2H, m), 7.85 (2H, m), 3.95 (2H, m), 1.36 (3H, s).

Step 2:2-(3,3,3-Trifluoro-2-methoxy-2-methylpropyl)isoindoline-1,3-dione

To a stirring solution of2-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)isoindoline-1,3-dione (250mg, 0.915 mmol)) at 0° C. in THF (8 ml), NaH (80 mg, 2 mmol) was added.After 30 minutes methyl iodide (1.299, 9.15 mmol) was added. Thereaction mixture was left stirring in a ice-bath and allowed to warm to25° C. over 3.5 hours. The reaction was quenched with sat. NH₄Cl and themixture extracted with DCM. The organic extract was separated using aphase separator and purification by chromatography on silica, eluting ina 0% to 30% iso-hexane:EtOAc afforded the title product; 1H NMR (400MHz, Methanol-d4) δ 7.91 (2H, m), 7.85 (2H, m), 3.97 (2H, m), 3.44 (3H,s), 1.42 (3H, s);

LC-MS: Rt 1.17 min; MS m/z 288.10 [M+H]+; Method 2 minLC_v003.

Step 3: 3,3,3-Trifluoro-2-methoxy-2-methylpropan-1-amine

A mixture comprising2-(3,3,3-trifluoro-2-methoxy-2-methylpropyl)isoindoline-1,3-dione (272mg, 0.95 mmol) and hydrazine (0.033 ml, 1.045 mmol) was stirred at 75°C. for 4 hours. After cooling to RT, the mixture was filtered and thefiltrate was concentrated in vacuo to afford the title product which wasused without further purification (no characterisation data available).

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention. Accordingly, the invention is notlimited except as by the appended claims.

EMBODIMENTS Consistory Clauses Embodiment 1

A compounds according to Formula I:

or pharmaceutically acceptable salts thereof, wherein:A is N or CR^(4a);R¹ is H; C₁-C₈ alkyl optionally substituted by one or more halogenatoms; C₂-C₈ alkenyl; C₂-C₈ alkynyl; C₃-C₁₀ cycloalkyl; C₅-C₁₀cycloalkenyl; —C₁-C₄ alkyl-C₃-C₈ cycloalkyl; C₁-C₈ alkoxy optionallysubstituted by one or more halogen atoms; halogen; SO₂NR⁸R⁹; SO₂R¹⁰;S—C₁-C₈alkyl optionally substituted by one or more halogen atoms;S—C₆-C₁₄ aryl; —(C₀-C₄ alkyl)-C₆-C₁₄ aryl; —(C₀-C₄ alkyl)-3 to 14membered heterocyclic group, wherein the heterocyclic group contains atleast one heteroatom selected from N, O and S; CN; NR¹¹R¹²; CONR¹³R¹⁴;NR¹³SO₂R¹⁵; NR¹³C(O)R¹⁵ and CO₂R¹⁵, wherein the cycloalkyl,cycloalkenyl, aryl and heterocyclyl groups are each optionallysubstituted by one or more Z substituents;R² is C₁-C₄ haloalkyl;R³, R⁴ and R^(4a) are each independently H or C₁-C₈ alkyl optionallysubstituted by one or more halogen atoms;R⁵ and R⁶ are each independently H; C₁-C₈ alkyl optionally substitutedby one or more halogen atoms; C₂-C₈ alkenyl; C₂-C₉ alkynyl; C₃-C₁₀cycloalkyl; C₅-C₁₀ cycloalkenyl; —C₁-C₄ alkyl-C₃-C₈ cycloalkyl; C₁-C₈alkoxy optionally substituted by one or more halogen atoms; OH; CN;halogen; —(C₀-C₄ alkyl)-C₆-C₁₄ aryl; —(C₀-C₄ alkyl)-3 to 14 memberedheterocyclic group, wherein the heterocyclic group contains at least oneheteroatom selected from N, O and S; or —(C₀-C₄ alkyl)-CO₂R¹⁵, whereinthe cycloalkyl, cycloalkenyl, —(C₀-C₄ alkyl)-C₆-C₁₄ aryl and —(C₀-C₄alkyl)-3 to 14 membered heterocyclic group groups are each optionallysubstituted by one or more Z substituents; orR⁵ and R⁶ are each independently a group of the formula:—(CH₂)_(m)—NR¹⁷R¹⁸; orR⁵ and R⁶ are each independently a group of the formula:—(CH₂)_(m)—OR⁴; orR⁴ and R⁵ together with the carbon atoms to which they are bound form a3 to 8 membered carbocyclic ring system; orR⁵ and R⁶ together with the carbon atoms to which they are bound form a5 to 8 membered carbocyclic ring system or a 5 to 8 memberedheterocyclic ring system containing one or more heteroatoms selectedfrom N, O and S, wherein the ring system is optionally substituted byone or more Z substituents;R⁴, R⁵ and R⁶ cannot all be the same;m is 0, 1, 2 or 3;R⁸, R¹¹, R¹³ and R¹⁷ are each independently H, C₁-C₈ alkyl optionallysubstituted by one or more halogen atoms, C₃-C₁₀ cycloalkyl or —(C₁-C₄alkyl)-C₃-C₈ cycloalkyl;R⁹, R¹⁰, R¹², R¹⁴, R¹⁵, R¹⁶ and R¹⁸ are each independently H; C₁-C₈alkyl optionally substituted by one or more halogen atoms; C₂-C₈alkenyl; C₂-C₈ alkynyl; C₃-C₁₀ cycloalkyl; C₅-C₁₀ cycloalkenyl; —C₁-C₄alkyl-C₃-C₈ cycloalkyl; —(C₀-C₄ alkyl)-C₆-C₁₄ aryl; or —(C₀-C₄ alkyl)-3to 14 membered heterocyclic group, wherein the heterocyclic groupcontains at least one heteroatom selected from N, O and S, wherein thecycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are eachoptionally substituted by one or more Z substituents; orR⁸ and R⁹, R¹¹ and R¹², R¹³ and R¹⁴, and R¹⁷ and R¹⁸ together with thenitrogen atom to which they are attached may form a 4 to 14 memberedheterocyclic group optionally substituted by one or more Z substituents;Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C₁-C₆ alkyloptionally substituted by one or more OH groups or NH₂ groups, C₁-C₆alkyl optionally substituted by one or more halogen atoms, C₁-C₆ alkoxyoptionally substituted by one or more OH groups or C₁-C₄ alkoxy,NR¹⁸(SO₂)R²¹, (SO₂)NR¹⁹R²¹, (SO₂)R²¹, NR¹⁸C(O)R²¹, C(O)NR¹⁹R²¹,NR¹⁸C(O)NR¹⁹R²¹, NR¹⁸C(O)OR¹⁹, NR¹⁹R²¹, C(O)OR¹⁹, C(O)R¹⁹, SR¹⁹, OR¹⁹,oxo, CN, NO₂, halogen or a 3 to 14 membered heterocyclic group, whereinthe heterocyclic group contains at least one heteroatom selected from N,O and S;R¹⁹ and R²¹ are each independently H; C₁-C₈ alkyl; C₃-C₈ cycloalkyl;C₁-C₄ alkoxy-C₁-C₄ alkyl; (C₀-C₄ alkyl)-aryl optionally substituted byone or more groups selected from C₁-C₆ alkyl, C₁-C₆ alkoxy and halogen;(C₀-C₄ alkyl)-3- to 14-membered heterocyclic group, the heterocyclicgroup including one or more heteroatoms selected from N, O and S,optionally substituted by one or more groups selected from halogen, oxo,C₁-C₆ alkyl and C(O)C₁-C₆ alkyl; (C₀-C₄ alkyl)-O-aryl optionallysubstituted by one or more groups selected from C₁-C₆ alkyl, C₁-C₈alkoxy and halogen; and (C₀-C₄ alkyl)-O-3- to 14-membered heterocyclicgroup, the heterocyclic group including one or more heteroatoms selectedfrom N, O and S, optionally substituted by one or more groups selectedfrom halogen, C₁-C₆ alkyl or C(O)C₁-C₆ alkyl; wherein the alkyl groupsare optionally substituted by one or more halogen atoms, C₁-C₄ alkoxy,C(O)NH₂, C(O)NHC₁-C₆ alkyl or C(O)N(C₁-C₆ alkyl)₂; or

R¹⁹ and R²¹ together with the nitrogen atom to which they attached forma 5- to 10-membered heterocyclic group, the heterocyclic group includingone or more further heteroatoms selected from N, O and S, theheterocyclic group being optionally substituted by one or moresubstituents selected from OH; halogen; aryl; 5- to 10-memberedheterocyclic group including one or more heteroatoms selected from N, Oand S; S(O)₂-aryl; S(O)₂—C₁-C₆ alkyl; C₁-C₆ alkyl optionally substitutedby one or more halogen atoms; C₁-C₆ alkoxy optionally substituted by oneor more OH groups or C₁-C₄ alkoxy; and C(O)OC₁-C₆ alkyl, wherein thearyl and heterocyclic substituent groups are themselves optionallysubstituted by C₁-C₆ alkyl, C₁-C₆ haloalkyl or C₁-C₆ alkoxy.

Embodiment 2

The compound of Formula I

or pharmaceutically acceptable salts thereof, wherein:A is N or CR^(4a);R¹ is H; C₁-C₈ alkyl optionally substituted by one or more halogenatoms; C₂-C₆ alkenyl; C₂-C₆ alkynyl; C₃-C₁₀ cycloalkyl; C₅-C₁₀cycloalkenyl; C₁-C₄ alkyl-C₃-C₈ cycloalkyl; C₁-C₈ alkoxy optionallysubstituted by one or more halogen atoms; halogen; SO₂NR⁸R⁹; SO₂R¹⁰;S—C₁-C₈alkyl optionally substituted by one or more halogen atoms;S—C₆-C₁₄ aryl; CN; NR¹¹R¹²; C(O)NR¹³R¹⁴; NR¹³SO₂R¹⁵; NR¹³C(O)R¹⁵,CO₂R¹⁵, —(C₀-C₄ alkyl)-C₆-C₁₄ aryl; or —(C₀-C₄ alkyl)-3 to 14 memberedheterocyclic group, wherein the heterocyclic group contains at least oneheteroatom selected from N, O and S; wherein the cycloalkyl,cycloalkenyl, aryl and heterocyclyl groups are each optionallysubstituted by one or more Z substituents;R² is C₁-C₄ haloalkyl;R³ and R^(4a) are each independently H or C₁-C₈ alkyl optionallysubstituted by one or more halogen atoms;R⁴ is H, or C₁-C₈ alkyl optional substituted with one or more halogen;R⁵ is —(CH₂), —NR¹⁷R¹⁸, —(CH₂)_(m)—OR′; C₁-C₈ alkoxy optionallysubstituted by one or more halogen atoms; —(C₀-C₄ alkyl)-CO₂R¹⁵; —(C₀-C₄alkyl)-C₆-C₁₄ aryl or -3 to 14 membered heterocyclic group, wherein theheterocyclic group contains at least one heteroatom selected from N, Oand S; wherein the —(C₀-C₄ alkyl)-C₆-C₁₄ aryl and —(C₀-C₄ alkyl)-3 to 14membered heterocyclic group are each optionally substituted by one ormore Z substituents;R⁶ is C₁-C₈ alkyl optionally substituted by one or more halogen atoms;C₃-C₁₀ cycloalkyl; —C₁-C₄ alkyl-C₃-C₈ cycloalkyl; C₁-C₈ alkoxyoptionally substituted by one or more halogen atoms; OH; CN; halogen;—(C₀-C₄ alkyl)-C₆-C₁₄ aryl; or —(C₀-C₄ alkyl)-3 to 14 memberedheterocyclic group, wherein the heterocyclic group contains at least oneheteroatom selected from N, O and S; wherein the cycloalkyl,cycloalkenyl, —(C₀-C₄ alkyl)-C₆-C₁₄ aryl and —(C₀-C₄ alkyl)-3 to 14membered heterocyclic group are each optionally substituted by one ormore Z substituents; orR⁶ is H, and R⁵ is —(CH₂)_(m)—NR¹⁷R¹⁸, —(CH₂)_(m)—OR′, C₁-C₈ alkoxyoptionally substituted by one or more halogen atoms; —(C₀-C₄alkyl)-C₆-C₁₄ aryl; —(C₀-C₄ alkyl)-3 to 14 membered heterocyclic group,wherein the heterocyclic group contains at least one heteroatom selectedfrom N, O and S; or —(C₀-C₄ alkyl)-CO₂R¹⁵, wherein —(C₀-C₄ alkyl)-C₈-C₁₄aryl and —(C₀-C₄ alkyl)-3 to 14 membered heterocyclic group groups areeach optionally substituted by one or more Z substituents; orR⁴ and R⁶ together with the carbon atoms to which they are bound form a3 to 8 membered carbocyclic ring system; orR⁴ and R⁵ together form an oxo group (C═O) and R⁶ is C₁-C₄ alkyloptionally substituted by one or more halogen atoms; C₁-C₄ alkoxyoptionally substituted by one or more halogen atoms; —(C₀-C₄alkyl)-C₆-C₁₄ aryl; or —(C₀-C₄ alkyl)-3 to 14 membered heterocyclicgroup, wherein the heterocyclic group contains at least one heteroatomselected from N, O and S, wherein the aryl and heterocyclyl groups areeach optionally substituted by one or more Z substituents; orR⁵ and R⁶ together with the carbon atoms to which they are bound a 5 to8 membered heterocyclic ring system containing one or more heteroatomsselected from N, O and S, wherein the ring system is optionallysubstituted by one or more Z substituents; orR⁴ and R⁵ and R⁶ together with the carbon atoms to which they are boundform a 5 to 8 membered heterocyclic ring system containing one or moreheteroatoms selected from N, O and S, wherein the ring system isoptionally substituted by one or more Z substituents;R′ is H, or C₁-C₈ alkyl optional substituted with one or more halogen;m is 0, 1, 2 or 3;R⁸, R¹¹, R¹³ and R¹⁷ are each independently H, C₁-C₈ alkyl optionallysubstituted by one or more halogen atoms, C₃-C₁₀ cycloalkyl or —(C₁-C₄alkyl)-C₃-C₈ cycloalkyl;R⁹, R¹⁰, R¹², R¹⁴, R¹⁵, R¹⁶ and R¹⁸ are each independently H; C₁-C₈alkyl optionally substituted by one or more halogen atoms; C₂-C₈alkenyl; C₂-C₈ alkynyl; C₃-C₁₀ cycloalkyl; C₅-C₁₀ cycloalkenyl; —C₁-C₄alkyl-C₃-C₈ cycloalkyl; —(C₀-C₄ alkyl)-C₆-C₁₄ aryl; or —(C₀-C₄ alkyl)-3to 14 membered heterocyclic group, wherein the heterocyclic groupcontains at least one heteroatom selected from N, O and S, wherein thecycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are eachoptionally substituted by one or more Z substituents; orR⁸ and R⁹, R¹¹ and R¹², R¹³ and R¹⁴, and R¹⁷ and R¹⁸ together with thenitrogen atom to which they are attached may form a 4 to 14 memberedheterocyclic group optionally substituted by one or more Z substituents;Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C₁-C₆ alkyloptionally substituted by one or more OH groups or NH₂ groups, C₁-C₆alkyl optionally substituted by one or more halogen atoms, C₁-C₆ alkoxyoptionally substituted by one or more OH groups or C₁-C₄ alkoxy,NR¹⁸(SO₂)R²¹, (SO₂)NR¹⁹R²¹, (SO₂)R²¹, NR¹⁸C(O)R²¹, C(O)NR¹⁹R²¹,NR¹⁸C(O)NR¹⁹R²¹, NR¹⁸C(O)OR¹⁹, NR¹⁹R²¹, C(O)OR¹⁹, C(O)R¹⁹, SR¹⁹, OR¹⁹,oxo, CN, NO₂, halogen or a 3 to 14 membered heterocyclic group, whereinthe heterocyclic group contains at least one heteroatom selected from N,O and S;R¹⁹ and R²¹ are each independently H; C₁-C₈ alkyl; C₃-C₈ cycloalkyl;C₁-C₄ alkoxy-C₁-C₄ alkyl; (C₀-C₄ alkyl)-aryl optionally substituted byone or more groups selected from C₁-C₆ alkyl, C₁-C₆ alkoxy and halogen;(C₀-C₄ alkyl)-3- to 14-membered heterocyclic group, the heterocyclicgroup including one or more heteroatoms selected from N, O and S,optionally substituted by one or more groups selected from halogen, oxo,C₁-C₆ alkyl and C(O)C₁-C₆ alkyl; (C₀-C₄ alkyl)-O-aryl optionallysubstituted by one or more groups selected from C₁-C₆ alkyl, C₁-C₆alkoxy and halogen; and (C₀-C₄ alkyl)-O-3- to 14-membered heterocyclicgroup, the heterocyclic group including one or more heteroatoms selectedfrom N, O and S, optionally substituted by one or more groups selectedfrom halogen, C₁-C₆ alkyl or C(O)C₁-C₆ alkyl; wherein the alkyl groupsare optionally substituted by one or more halogen atoms, C₁-C₄ alkoxy,C(O)NH₂, C(O)NHC₁-C₆ alkyl or C(O)N(C₁-C₆ alkyl)₂; orR¹⁹ and R²¹ together with the nitrogen atom to which they attached forma 5- to 10-membered heterocyclic group, the heterocyclic group includingone or more further heteroatoms selected from N, O and S, theheterocyclic group being optionally substituted by one or moresubstituents selected from OH; halogen; aryl; 5- to 10-memberedheterocyclic group including one or more heteroatoms selected from N, Oand S; S(O)₂-aryl; S(O)₂—C₁-C₆alkyl; C₁-C₆ alkyl optionally substitutedby one or more halogen atoms; C₁-C₆ alkoxy optionally substituted by oneor more OH groups or C₁-C₄ alkoxy; and C(O)OC₁-C₆ alkyl, wherein thearyl and heterocyclic substituent groups are themselves optionallysubstituted by C₁-C₆ alkyl, C₁-C₆ haloalkyl or C₁-C₆ alkoxy.

Embodiment 3

The compound according to embodiment 1 or 2, wherein

-   -   R¹ is H; C₁-C₄ alkyl optionally substituted by one or more        halogen atoms; C₁-C₄ alkoxy optionally substituted by one or        more halogen atoms; halogen; C₆-C₁₄ aryl; —(C₀-C₄ alkyl)-3 to 14        membered heterocyclic group, wherein the heterocyclic group        contains at least one heteroatom selected from N, O and S; or        —NR¹¹R¹², wherein the aryl and heterocyclic groups are each        optionally substituted by one or more Z substituents.

Embodiment 4

The compound according to embodiment 1 to 3, wherein

-   -   R¹ is C₁-C₄ alkyl optional substituted by one or more halogen        atoms.

Embodiment 5

The compound according to embodiment 1 to 4, wherein

-   -   R¹ is —CH₃ or CF₃.

Embodiment 6

The compound according to embodiment 1, 2 or 3, wherein

-   -   R¹ is C₁-C₄ alkoxy optional substituted by one or more halogen        atoms.

Embodiment 7

The compound according to embodiment 1, 2, 3 or 6, wherein

-   -   R¹ is —OCH₃, —OCH₂CH₃ or —OCF₃.

Embodiment 8

The compound according to embodiments 1, 2 or 3, wherein R¹ is aryl,wherein aryl is phenyl optionally substituted by one or more Zsubstituents,

Embodiment 9

The compound according to embodiment 1, 2, 3 or 8, wherein R¹ is4-fluorophenyl, 4-chloro-2-methylphenyl, or 2,4-dichlorophenyl.

Embodiment 10

The compound according to embodiment 1, 2 or 3, wherein R¹ is pyridyl,oxazole, pyrrolidine or pyrazole and is optionally substituted by one ormore Z substituents.

Embodiment 11

The compound according to embodiment 1, 2, 3 or 10, wherein R¹ is1-methyl-4-pyridyl, oxzaoyl-2-yl, 1-methyl-1H-pyrazole-4-yl orpyrrolidin-1yl.

Embodiment 12

The compound according to embodiment 1 to 11, wherein R¹ is Br, —CH₃,—CF₃, —OCH₃, —OCH₂CH₃, —OCF₃, 4-fluorophenyl, 4-chloro-2-methylphenyl,2,4-dichlorophenyl, 1-methyl-4-pyridyl, 1-methyl-1H-pyrazole-4-yl,oxzaoyl-2-yl, or pyrrolidin-1-yl.

Embodiment 13

The compound according to embodiment 1 to 12, wherein R⁵ provides aheteroatom two carbons from the amide nitrogen, wherein the heteroatomis oxygen or nitrogen.

Embodiment 14

The compound according to embodiment 1 to 13, wherein

-   -   R⁴ is H or C₁-C₄ alkyl optionally substituted by one or more        halogen atoms;    -   R⁵ is C₁-C₄ alkoxy optionally substituted by one or more halogen        atoms; —(CH₂)_(m)—NR¹⁷R¹⁸; —(CH₂)_(m)—OR′, or OH;    -   R′ is H, or C₁-C₄ alkyl optional substituted with one or more        halogen;    -   m is 0, 1 or 2;    -   R⁶ is C₁-C₄ alkyl optionally substituted by one or more halogen        atoms; C₁-C₄ alkoxy optionally substituted by one or more        halogen atoms; OH; CN; halogen; —(C₀-C₄ alkyl)-C₆ aryl; or        —(C₀-C₄ alkyl)-5 to 6 membered heterocyclic group, wherein the        heterocyclic group contains at least one heteroatom selected        from N, O and S, wherein the aryl and heterocyclyl groups are        each optionally substituted by one or more Z substituents; or    -   R⁴ and R⁶ together with the carbon atoms to which they are bound        form a 3 to 8 membered carbocyclic ring system; or    -   R⁵ and R⁶ together with the carbon atoms to which they are bound        a 5 to 8 membered heterocyclic ring system containing one or        more heteroatoms selected from N, O and S, wherein the ring        system is optionally substituted by one or more Z substituents;    -   R¹⁷ and R¹⁸ are each independently H; or C₁-C₄ alkyl optionally        substituted by one or more halogen atoms.

Embodiment 15

The compound according to any proceeding embodiment, wherein

-   -   R³ is H;    -   R⁴ is H or Me;    -   R^(4a) is H;    -   R⁵ is —(CH₂)_(m)—NR¹⁷R¹⁸; —(CH₂)_(m)—OR′; or OH;    -   m is 0, or 1;    -   R′ is H;    -   R⁶ is C₁-C₄ alkyl optionally substituted by one or more halogen        atoms; or    -   R⁵ and R⁶ together with the carbon atoms to which they are bound        form a 5 to 6 membered heterocyclic ring system containing one        or more heteroatoms selected from N, O and S, wherein the ring        system is optionally substituted by one or more Z substituents;        and    -   R¹⁷ and R¹⁸ are each independently H; or C₁-C₄ alkyl optionally        substituted by one or more halogen atoms.

Embodiment 16

The compound according to any proceeding embodiment, wherein

-   -   R³ is H;    -   R⁴ is H or Me;    -   R^(4a) is H;    -   R⁵ is —NR¹⁷R¹⁸; or OH;    -   R⁶ is C₁-C₄ alkyl optionally substituted by one or more halogen        atoms; or    -   R⁵ and R⁶ together with the carbon atoms to which they are bound        form a 5 to 6 membered heterocyclic ring system containing one        or more heteroatoms selected from N, O and S, wherein the ring        system is optionally substituted by one or more Z substituents;        and    -   R¹⁷ and R¹⁸ are each independently H; or C₁-C₄ alkyl optionally        substituted by one or more halogen atoms.

Embodiment 17

The compound according to any proceeding claim, wherein

-   -   R³ is H;    -   R⁴ is H or Me;    -   R^(4a) is H;    -   R⁵ is —NR¹⁷R¹⁸, or OH;    -   R⁶ is C₁-C₄ alkyl optionally substituted by one or more halogen        atoms; and    -   R¹⁷ and R¹⁸ are each independently H; or C₁-C₄ alkyl optionally        substituted by one or more halogen atoms.

Embodiment 18

The compound according to embodiment 1 to 13, wherein

-   -   R³ is H;    -   R^(4a) is H;    -   R⁴ and R⁵ form an oxo group;    -   R⁶ is C₁-C₄ alkyl optionally substituted by one or more halogen        atoms; C₁-C₄ alkoxy optionally substituted by one or more        halogen atoms; phenyl; or 5 to 6 membered heterocyclic group,        wherein the heterocyclic group contains at least one heteroatom        selected from N, O and S, wherein the phenyl and heterocyclyl        groups are each optionally substituted by one or more Z        substituents.

Embodiment 19

The compound according to embodiment 1 to 13 or 18, wherein

-   -   R³ is H;    -   R^(4a) is H;    -   R⁴ and R⁵ form an oxo group;    -   R⁶ is C₁-C₄ alkyl optionally substituted by one or more halogen        atoms; or phenyl, wherein the phenyl is optionally substituted        by one or more Z substituents;    -   Z is independently OH, C₁-C₄ alkyl optionally substituted by one        or more OH groups or NH₂ groups, C₁-C₄ alkyl optionally        substituted by one or more halogen atoms, C₁-C₄ alkoxy        optionally substituted by one or more OH groups or C₁-C₄ alkoxy,        C(O)OR¹⁹, C(O)R¹⁹, OR¹⁹, CN, or halogen;    -   R¹⁹ is H; C₁-C₄ alkyl; C₃-C₆ cycloalkyl; or C₁-C₄ alkoxy-C₁-C₄        alkyl, wherein all alkyl are optionally substituted with        halogens.

Embodiment 20

The compound according to embodiment 1 to 13 or 18 to 19, wherein

-   -   R³ is H;    -   R^(4a) is H;    -   R⁴ and R⁵ form an oxo group;    -   R⁶ is C₁-C₄ alkyl optionally substituted by one or more halogen        atoms; or phenyl, wherein the phenyl is optionally substituted        by one or more Z substituents;    -   Z is independently, C₁-C₄ alkyl optionally substituted by one or        more halogen atoms, C₁-C₄ alkoxy or halogen.

Embodiment 21

The compound according to embodiment 1 to 13, wherein the compound isrepresented by formula II,

or a pharmaceutically acceptable salt thereof,wherein,R¹⁰¹ is selected from the following:

Embodiment 22

The compound according to embodiment 21, wherein

-   -   R³ is H;    -   R¹⁰¹ is

Embodiment 23

The compound according to embodiment 21, wherein

-   -   R³ is H;    -   R¹⁰¹ is

Embodiment 24

The compound according to embodiment 21, wherein

-   -   R³ is H;    -   R¹⁰¹ is

Embodiment 25

The compound according to embodiment 21, wherein

-   -   R³ is H;    -   R¹⁰¹ is

Embodiment 26

The compound according to embodiment 1 to 13, wherein

-   -   R³ is H;    -   R¹⁰¹ is —(C₁-C₂ (C₁-C₂ alkyl)-5 to 10 membered heterocyclic        group, wherein the heterocyclic group contains at least one        heteroatom selected from N, O and S, wherein the aryl and        heterocyclyl groups are each optionally substituted by one or        more Z substituents.

Embodiment 27

The compound according to embodiment 21 or 26, wherein

-   -   R³ is H;    -   R¹⁰¹ is

Embodiment 28

The compound of formula III

or pharmaceutically acceptable salts thereof, wherein:A is N or CR^(4a);X is NR^(y) or O;R¹ is C₁-C₈ alkyl optionally substituted by one or more halogen atoms;C₃-C₁₀ cycloalkyl; —C₁-C₄ alkyl-C₃-C₈ cycloalkyl; C₁-C₈ alkoxyoptionally substituted by one or more halogen atoms; halogen; CN;NR¹¹R¹²; C(O)NR¹³R¹⁴; NR¹³C(O)R¹⁵, CO₂R¹⁵, —(C₀-C₄ alkyl)-C₆-C₁₄ aryl;or —(C₀-C₄ alkyl)-3 to 14 membered heterocyclic group, wherein theheterocyclic group contains at least one heteroatom selected from N, Oand S; wherein the cycloalkyl, aryl and heterocyclyl groups are eachoptionally substituted by one or more Z substituents;R² is C₁-C₄ haloalkyl;R³ and R^(4a) are each independently H or C₁-C₈ alkyl optionallysubstituted by one or more halogen atoms;R⁴ is H, or C₁-C₈ alkyl optional substituted with one or more halogen;R^(5a) is H, C₁-C₈ alkyl optional substituted with one or more halogen,—(C₀-C₄ alkyl)-C₆-C₁₄ aryl or -3 to 14 membered heterocyclic group,wherein the heterocyclic group contains at least one heteroatom selectedfrom N, O and S; wherein the —(C₀-C₄ alkyl)-C₆-C₁₄ aryl and —(C₀-C₄alkyl)-3 to 14 membered heterocyclic group are each optionallysubstituted by one or more Z substituents;R^(y) is H, C₁-C₈ alkyl optional substituted with one or more halogen,—(C₀-C₄ alkyl)-C₆-C₁₄ aryl or -3 to 14 membered heterocyclic group,wherein the heterocyclic group contains at least one heteroatom selectedfrom N, O and S; wherein the —(C₀-C₄ alkyl)-C₆-C₁₄ aryl and —(C₀-C₄alkyl)-3 to 14 membered heterocyclic group are each optionallysubstituted by one or more Z substituents;R⁶ is C₁-C₈ alkyl optionally substituted by one or more halogen atoms;C₃-C₁₀ cycloalkyl; —C₁-C₄ alkyl-C₃-C₈ cycloalkyl; C₁-C₈ alkoxyoptionally substituted by one or more halogen atoms; OH; CN; halogen;—(C₀-C₄ alkyl)-C₆-C₁₄ aryl; or —(C₀-C₄ alkyl)-3 to 14 memberedheterocyclic group, wherein the heterocyclic group contains at least oneheteroatom selected from N, O and S; wherein the cycloalkyl,cycloalkenyl, —(C₀-C₄ alkyl)-C₆-C₁₄ aryl and —(C₀-C₄ alkyl)-3 to 14membered heterocyclic group are each optionally substituted by one ormore Z substituents; orR⁴ and R⁶ together with the carbon atoms to which they are bound form a3 to 8 membered carbocyclic ring system; orR^(5a) and R⁶ together with the atoms to which they are bound a 5 to 8membered heterocyclic ring system containing one or more heteroatomsselected from N, O and S, wherein the ring system is optionallysubstituted by one or more Z substituents; orR^(5a) and R^(y) together with the atoms to which they are bound a 5 to8 membered heterocyclic ring system containing one or more heteroatomsselected from N, O and S, wherein the ring system is optionallysubstituted by one or more Z substituents;R¹¹ and R¹³ are each independently H, C₁-C₈ alkyl optionally substitutedby one or more halogen atoms, C₃-C₁₀ cycloalkyl or —(C₁-C₄ alkyl)-C₃-C₈cycloalkyl;R¹², R¹⁴, and R¹⁵ are each independently H; C₁-C₈ alkyl optionallysubstituted by one or more halogen atoms; C₂-C₈ alkenyl; C₂-C₈ alkynyl;C₃-C₁₀ cycloalkyl; C₅-C₁₀ cycloalkenyl; —C₁-C₄ alkyl-C₃-C₈ cycloalkyl;—(C₀-C₄ alkyl)-C₆-C₁₄ aryl; or —(C₀-C₄ alkyl)-3 to 14 memberedheterocyclic group, wherein the heterocyclic group contains at least oneheteroatom selected from N, O and S, wherein the cycloalkyl,cycloalkenyl, aryl and heterocyclyl groups are each optionallysubstituted by one or more Z substituents; orR¹¹ and R¹², and R¹³ and R¹⁴ together with the nitrogen atom to whichthey are attached may form a 4 to 14 membered heterocyclic groupoptionally substituted by one or more Z substituents;Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C₁-C₆ alkyloptionally substituted by one or more OH groups or NH₂ groups, C₁-C₆alkyl optionally substituted by one or more halogen atoms, C₁-C₆ alkoxyoptionally substituted by one or more OH groups or C₁-C₄ alkoxy,NR¹⁸(SO₂)R²¹, (SO₂)NR¹⁹R²¹, (SO₂)R²¹, NR¹⁸C(O)R²¹, C(O)NR¹⁹R²¹,NR¹⁸C(O)NR¹⁹R²¹, NR¹⁸C(O)OR¹⁹, NR¹⁹R²¹, C(O)OR¹⁹, C(O)R¹⁹, SR¹⁹, OR¹⁹,oxo, CN, NO₂, halogen or a 3 to 14 membered heterocyclic group, whereinthe heterocyclic group contains at least one heteroatom selected from N,O and S;R¹⁹ and R²¹ are each independently H; C₁-C₈ alkyl; C₃-C₈ cycloalkyl;C₁-C₄ alkoxy-C₁-C₄ alkyl; (C₀-C₄ alkyl)-aryl optionally substituted byone or more groups selected from C₁-C₆ alkyl, C₁-C₆ alkoxy and halogen;(C₀-C₄ alkyl)-3- to 14-membered heterocyclic group, the heterocyclicgroup including one or more heteroatoms selected from N, O and S,optionally substituted by one or more groups selected from halogen, oxo,C₁-C₆ alkyl and C(O)C₁-C₆ alkyl; (C₀-C₄ alkyl)-O-aryl optionallysubstituted by one or more groups selected from C₁-C₆ alkyl, C₁-C₆alkoxy and halogen; and (C₀-C₄ alkyl)-O-3- to 14-membered heterocyclicgroup, the heterocyclic group including one or more heteroatoms selectedfrom N, O and S, optionally substituted by one or more groups selectedfrom halogen, C₁-C₆ alkyl or C(O)C₁-C₆ alkyl; wherein the alkyl groupsare optionally substituted by one or more halogen atoms, C₁-C₄ alkoxy,C(O)N C(O)NHC₁-C₆ alkyl or C(O)N(C₁-C₆ alkyl)₂; orR¹⁹ and R²¹ together with the nitrogen atom to which they attached forma 5- to 10-membered heterocyclic group, the heterocyclic group includingone or more further heteroatoms selected from N, O and S, theheterocyclic group being optionally substituted by one or moresubstituents selected from OH; halogen; aryl; 5- to 10-memberedheterocyclic group including one or more heteroatoms selected from N, Oand S; S(O)₂-aryl; S(O)₂—C₁-C₆alkyl; C₁-C₆ alkyl optionally substitutedby one or more halogen atoms; C₁-C₆ alkoxy optionally substituted by oneor more OH groups or C₁-C₄ alkoxy; and C(O)OC₁-C₆ alkyl, wherein thearyl and heterocyclic substituent groups are themselves optionallysubstituted by C₁-C₆ alkyl, C₁-C₆ haloalkyl or C₁-C₆ alkoxy.

Embodiment 29

The compound according to embodiment 28, wherein

A is N or CR^(4a);

X is NR^(y) or O;

R¹ is C₁-C₄ alkyl optionally substituted by one or more halogen atoms;C₁-C₄ alkoxy optionally substituted by one or more halogen atoms;halogen; —(C₀-C₄ alkyl)-C₆ aryl; or —(C₀-C₄ alkyl)-5 to 6 memberedheterocyclic group, wherein the heterocyclic group contains at least oneheteroatom selected from N, O and S; wherein the cycloalkyl, aryl andheterocyclyl groups are each optionally substituted by one or more Zsubstituents;R² is C₁-C₄ haloalkyl;R³ and R^(4a) are H;R⁴ is H, or C₁-C₄ alkyl optional substituted with one or more halogen;R^(5a) is H, C₁-C₄ alkyl optional substituted with one or more halogen,—(C₀-C₄ alkyl)-C₆ aryl or -5 to 8 membered heterocyclic group, whereinthe heterocyclic group contains at least one heteroatom selected from N,O and S; wherein the —(C₀-C₄ alkyl)-C₆ aryl and -5 to 8 memberedheterocyclic group are each optionally substituted by one or more Zsubstituents;R^(y) is H, C₁-C₄ alkyl optional substituted with one or more halogen,—(C₀-C₄ alkyl)-C₆ aryl or -5 to 8 membered heterocyclic group, whereinthe heterocyclic group contains at least one heteroatom selected from N,O and S; wherein the —(C₀-C₄ alkyl)-C₆ aryl and -5 to 8 memberedheterocyclic group are each optionally substituted by one or more Zsubstituents;R⁶ is C₁-C₄ alkyl optionally substituted by one or more halogen atoms;C₁-C₄ alkoxy optionally substituted by one or more halogen atoms; OH;CN; —(C₀-C₄ alkyl)-C₆ aryl; or -5 to 8 membered heterocyclic group,wherein the heterocyclic group contains at least one heteroatom selectedfrom N, O and S; wherein the —C₆ aryl and -5 to 8 membered heterocyclicgroup are each optionally substituted by one or more Z substituents; orR⁴ and R⁶ together with the carbon atoms to which they are bound form a3 to 8 membered carbocyclic ring system; orR^(5a) and R⁶ together with the atoms to which they are bound a 5 to 8membered heterocyclic group containing one or more heteroatoms selectedfrom N, O and S, wherein the heterocyclic group is optionallysubstituted by one or more Z substituents; orR^(5a) and R^(y) together with the atoms to which they are bound a 5 to8 membered heterocyclic ring system containing one or more heteroatomsselected from N, O and S, wherein the ring system is optionallysubstituted by one or more Z substituents;Z is independently OH, aryl, O-aryl, C₁-C₆ alkyl optionally substitutedby one or more OH groups or NH₂ groups, C₁-C₆ alkyl optionallysubstituted by one or more halogen atoms, C₁-C₆ alkoxy optionallysubstituted by one or more OH groups or C₁-C₄ alkoxy, NR¹⁸C(O)R²¹,C(O)NR¹⁹R²¹, NR¹⁹R²¹, C(O)OR¹⁹, C(O)R¹⁹, SR¹⁹, OR¹⁹, oxo, CN, NO₂,halogen or a 5 to 8 membered heterocyclic group, wherein theheterocyclic group contains at least one heteroatom selected from N, Oand S; wherein the heterocyclic group is option substituted by halogen,C₁-C₄ alkyl optionally substituted by halogen, C₁-C₄ alkoxy or —CN;R¹⁸ is H or C₁-C₄ alkyl;R¹⁹ and R²¹ are each independently H; C₁-C₈ alkyl; C₃-C₈ cycloalkyl;C₁-C₄ alkoxy-C₁-C₄ alkyl; (C₀-C₄ alkyl)-aryl optionally substituted byone or more groups selected from C₁-C₆ alkyl, C₁-C₆ alkoxy and halogen;(C₀-C₄ alkyl)-3- to 14-membered heterocyclic group, the heterocyclicgroup including one or more heteroatoms selected from N, O and S,optionally substituted by one or more groups selected from halogen, oxo,C₁-C₆ alkyl and C(O)C₁-C₆ alkyl; (C₀-C₄ alkyl)-O-aryl optionallysubstituted by one or more groups selected from C₁-C₆ alkyl, C₁-C₆alkoxy and halogen; and (C₀-C₄ alkyl)-O-3- to 14-membered heterocyclicgroup, the heterocyclic group including one or more heteroatoms selectedfrom N, O and S, optionally substituted by one or more groups selectedfrom halogen, C₁-C₆ alkyl or C(O)C₁-C₆ alkyl; wherein the alkyl groupsare optionally substituted by one or more halogen atoms, C₁-C₄ alkoxy,C(O)N C(O)NHC₁-C₆ alkyl or C(O)N(C₁-C₆ alkyl)₂; orR¹⁹ and R²¹ together with the nitrogen atom to which they attached forma 5- to 10-membered heterocyclic group, the heterocyclic group includingone or more further heteroatoms selected from N, O and S, theheterocyclic group being optionally substituted by one or moresubstituents selected from OH; halogen; aryl; 5- to 10-memberedheterocyclic group including one or more heteroatoms selected from N, Oand S; S(O)₂-aryl; S(O)₂—C₁-C₆ alkyl; C₁-C₆ alkyl optionally substitutedby one or more halogen atoms; C₁-C₆ alkoxy optionally substituted by oneor more OH groups or C₁-C₄ alkoxy; and C(O)OC₁-C₆ alkyl, wherein thearyl and heterocyclic substituent groups are themselves optionallysubstituted by C₁-C₆ alkyl, C₁-C₆ haloalkyl or C₁-C₆ alkoxy.

Embodiment 30

The compound according to embodiment 28 or 29, wherein

A is N or CR^(4a);

X is NR^(y) or O;

R¹ is C₁-C₄ alkyl optionally substituted by one or more halogen atoms;C₁-C₄ alkoxy optionally substituted by one or more halogen atoms; orhalogen;

R² is CF₃;

R³ and R^(4a) are H;

R⁴ is H, or C₁-C₄ alkyl optional substituted with one or more halogen;

R^(5a) is H, C₁-C₄ alkyl optional substituted with one or more halogen,

R^(y) is H, C₁-C₄ alkyl optional substituted with one or more halogen,

R⁶ is C₁-C₄ alkyl optionally substituted by one or more halogen atoms;C₁-C₄ alkoxy optionally substituted by one or more halogen atoms; OH;CN; or

R⁴ and R⁶ together with the carbon atoms to which they are bound form a3 to 6 membered carbocyclic ring system; or

R^(5a) and R⁶ together with the atoms to which they are bound a 5 to 8membered heterocyclic group containing one or more heteroatoms selectedfrom N, O and S, wherein the heterocyclic group is optionallysubstituted by one or more Z substituents; or

R^(5a) and R^(y) together with the atoms to which they are bound a 5 to8 membered heterocyclic ring system containing one or more heteroatomsselected from N, O and S, wherein the ring system is optionallysubstituted by one or more Z substituents;

Z is independently OH, C₁-C₆ alkyl optionally substituted by one or moreOH groups or NH₂ groups, C₁-C₆ alkyl optionally substituted by one ormore halogen atoms, C₁-C₆ alkoxy optionally substituted by one or moreOH groups or C₁-C₄ alkoxy, NR¹⁹R²¹, C(O)OR¹⁹, C(O)R¹⁹, SR¹⁹, OR¹⁹, oxo,CN, NO₂, or halogen;R¹⁹ is H; C₁-C₈ alkyl; (C₀-C₄ alkyl)-aryl optionally substituted by oneor more groups selected from C₁-C₆ alkyl, C₁-C₆ alkoxy and halogen;(C₀-C₄ alkyl)-3- to 14-membered heterocyclic group, the heterocyclicgroup including one or more heteroatoms selected from N, O and S,optionally substituted by one or more groups selected from halogen, oxo,C₁-C₆ alkyl and C(O)C₁-C₆ alkyl; (C₀-C₄ alkyl)-O-aryl optionallysubstituted by one or more groups selected from C₁-C₆ alkyl, C₁-C₆alkoxy and halogen; and (C₀-C₄ alkyl)-O-3- to 14-membered heterocyclicgroup, the heterocyclic group including one or more heteroatoms selectedfrom N, O and S, optionally substituted by one or more groups selectedfrom halogen, C₁-C₆ alkyl or C(O)C₁-C₆ alkyl; wherein the alkyl groupsare optionally substituted by one or more halogen atoms, C₁-C₄ alkoxy,C(O)NH₂, C(O)NHC₁-C₆ alkyl or C(O)N(C₁-C₆ alkyl)₂; orR¹⁹ and R²¹ together with the nitrogen atom to which they attached forma 5- to 6-membered heterocyclic group, the heterocyclic group includingone or more further heteroatoms selected from N, O and S, theheterocyclic group being optionally substituted by one or moresubstituents selected from OH; halogen; aryl; 5- to 10-memberedheterocyclic group including one or more heteroatoms selected from N, Oand S; S(O)₂-aryl; S(O)₂—C₁-C₆ alkyl; C₁-C₆ alkyl optionally substitutedby one or more halogen atoms; C₁-C₆ alkoxy optionally substituted by oneor more OH groups or C₁-C₄ alkoxy; and C(O)OC₁-C₆ alkyl, wherein thearyl and heterocyclic substituent groups are themselves optionallysubstituted by C₁-C₆ alkyl, C₁-C₆ haloalkyl or C₁-C₆ alkoxy.

Embodiment 31

The compound according to embodiment 28 to 30, wherein

A is N or CR^(4a);

X is NR^(y) or O;

R¹ is C₁-C₄ alkyl optionally substituted by one or more halogen atoms;C₁-C₄ alkoxy optionally substituted by one or more halogen atoms; orhalogen;

R² is CF₃;

R³ and R^(4a) are H;

R⁴ is H, or C₁-C₄ alkyl optional substituted with one or more halogen;

R^(5a) is H, C₁-C₄ alkyl optional substituted with one or more halogen,

R^(y) is H, C₁-C₄ alkyl optional substituted with one or more halogen,

R⁶ is C₁-C₄ alkyl optionally substituted by one or more halogen atoms;C₁-C₄ alkoxy optionally substituted by one or more halogen atoms; OH;CN; or

R^(5a) and R⁶ together with the atoms to which they are bound a 5 to 8membered heterocyclic group containing one or more heteroatoms selectedfrom N, O and S, wherein the heterocyclic group is optionallysubstituted by one or more Z substituents; or

R^(5a) and R^(y) together with the atoms to which they are bound a 5 to8 membered heterocyclic ring system containing one or more heteroatomsselected from N, O and S, wherein the ring system is optionallysubstituted by one or more Z substituents;

Z is independently OH, C₁-C₆ alkyl optionally substituted by one or moreOH groups or NH₂ groups, C₁-C₆ alkyl optionally substituted by one ormore halogen atoms, C₁-C₆ alkoxy optionally substituted by one or moreOH groups or C₁-C₄ alkoxy, oxo, CN, NO₂, or halogen;

Embodiment 32

The compound according to any of the proceeding embodiments, A is N.

Embodiment 33

The compound to embodiments 1 to 31, wherein A is CR^(4a).

Embodiment 34

The compound according to embodiment 33, wherein A is CR^(4a) and R^(4a)is H.

Embodiment 35

The compound according to any proceeding embodiment, wherein R² isCF₃CF₂—, (CF₃)₂CH—, CH₃—CF₂—, CF₃CF₂—, CF₃, CF₂H—, CH₃—CCl₂—,CF₃CFCClH—, CBr₃, CBr₂H—CF₃CF₂CHCF₃ or CF₃CF₂CF₂CF₂—.

Embodiment 36

The compound according to any proceeding embodiment, wherein R² is CF₃.

Embodiment 37

The compound according to any proceeding embodiment, wherein thecompound is a substantially pure enantiomer with the S configuration.

Embodiment 38

The compound according to embodiment 1 to 36, wherein the compound is asubstantially pure enantiomer with the R configuration.

Embodiment 39

The compound according to embodiment 2, 21 or 28, wherein the compoundis represented by:

-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    (3,3,3-trifluoro-2-hydroxy-propyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    ((S)-3,3,3-trifluoro-2-hydroxy-propyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    [(R)-1-(tetrahydro-furan-2-yl)methyl]-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    ([1,3]dioxolan-2-ylmethyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    [(S)-1-(tetrahydro-furan-2-yl)methyl]amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    (tetrahydro-furan-2-ylmethyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    (2-methyl-2-piperidin-1-yl-propyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    (2-hydroxy-propyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    (2-hydroxy-2-methyl-propyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    (2-methyl-tetrahydro-furan-2-yl-methyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    (2-methoxy-ethyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    [2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethyl]-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    (2-morpholin-4-yl-2-phenyl-ethyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    (2-dimethylamino-2-phenyl-ethyl)-amide;-   3-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic    acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;-   3-Amino-5-trifluoromethyl-pyridine-2-carboxylic acid    (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;-   3-Amino-6-(4-chloro-2-methyl-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic    acid ((R)-3,3,3-trifluoro-2-hydroxy-propyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    (3,3,3-trifluoro-2-hydroxy-2-trifluoromethyl-propyl)-amide;-   5-Amino-6′-methyl-3-trifluoromethyl-[2,3′]bipyridinyl-6-carboxylic    acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;-   3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid    (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;-   3-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic    acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;-   3-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic    acid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;-   3-amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic    acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;-   3-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic    acid (2-hydroxy-2-methyl-propyl)-amide;-   3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid    (3,3,3-trifluoro-2-hydroxy-propyl)-amide;-   5-Amino-6′-methyl-3-trifluoromethyl-[2,3′]bipyridinyl-6-carboxylic    acid (3,3,3-trifluoro-2-hydroxy-2-trifluoromethyl-propyl)-amide;-   5-Amino-6′-methyl-3-trifluoromethyl-[2,3′]bipyridinyl-6-carboxylic    acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;-   3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid    ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;-   3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid    ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;-   3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid    ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;-   3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid    ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;-   Methyl    3-(3-amino-6-bromo-5-(trifluoromethyl)picolinamido)propanoate;-   3-Amino-N-(benzo[d]isoxazol-3-ylmethyl)-6-bromo-5-(trifluoromethyl)    picolinamide;-   3-Amino-6-(oxazol-2-yl)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide;-   3-Amino-6-bromo-N-(3,3,3-trifluoro-2-methoxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide;-   3-amino-N-(2-hydroxy-3-methyl-2-(trifluoromethyl)butyl)-6-methoxy-5-(trifluoromethyl)picolinamide;-   3-Amino-6-cyclopropyl-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide;-   3-Amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propyl)-5-(trifluoro    methyl)picolinamide;-   5-amino-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-3-(trifluoromethyl)-2,4′-bipyridine-6-carboxamide;-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    (3-methyl-2-oxo-butyl)-amide;-   3-Amino-6-(1-methyl-1H-pyrazol-4-yl)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide;-   (S)-3-amino-6-ethoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoro    methyl)picolinamide;-   3-Amino-6-(pyrrolidin-1-yl)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide;-   3-Amino-N-(2-amino-3,3,3-trifluoro-2-methylpropyl)-6-methoxy-5-(trifluoromethyl)    picolinamide; or-   3-Amino-6-methoxy-N-(3,3,3-trifluoro-2-(4-methoxybenzylamino)-2-methylpropyl)-5-(trifluoromethyl)picolinamide.

Embodiment 40

The compound according to embodiment 39, wherein the compound is

-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    [(R)-1-(tetrahydro-furan-2-yl)methyl]-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    ([1,3]dioxolan-2-ylmethyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    [(S)-1-(tetrahydro-furan-2-yl)methyl]-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    (tetrahydro-furan-2-ylmethyl)-amide; or-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    (2-methyl-tetrahydro-furan-2-yl-methyl)-amide.

Embodiment 41

The compound according to embodiment 2, 21 or 28, wherein the compoundis

-   3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid    [2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethyl]-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    [2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethyl]-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    (2-morpholin-4-yl-2-phenyl-ethyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    (2-dimethylamino-2-phenyl-ethyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid    (3-methyl-2-morpholin-4-yl-butyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid    (2-methyl-2-morpholin-4-yl-propyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid    (1-morpholin-4-yl-cyclohexylmethyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid    (2-morpholin-4-yl-2-phenyl-ethyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid    (2-dimethylamino-2-phenyl-ethyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid    [2-(4-methoxy-phenyl)-2-pyrrolidin-1-yl-ethyl]-amide;-   3-Amino-N-(2-amino-3,3,3-trifluoro-2-methylpropyl)-6-methoxy-5-(trifluoromethyl)    picolinamide; or-   3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid    [2-dimethylamino-2-(4-methoxy-phenyl)-ethyl]-amide.

Embodiment 42

The compound according to embodiment 2, 21 or 28, wherein the compoundis

-   3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid    (2-methyl-tetrahydro-furan-2-yl-methyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid    [2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethyl]-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid    (3-methyl-2-morpholin-4-yl-butyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid    (2-methyl-2-morpholin-4-yl-propyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid    (1-morpholin-4-yl-cyclohexylmethyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid    (2-morpholin-4-yl-2-phenyl-ethyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid    (2-dimethylamino-2-phenyl-ethyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid    [2-(4-methoxy-phenyl)-2-pyrrolidin-1-yl-ethyl]-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid    [2-dimethylamino-2-(4-methoxy-phenyl)-ethyl]-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid    [2-(4-fluoro-phenyl)-2-oxo-ethyl]-amide;-   3-Amino-6-furan-2-yl-5-trifluoromethyl-pyrazine-2-carboxylic acid    [2-(2-methoxy-phenyl)-ethyl]-amide;-   3-amino-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5,6-bis(trifluoromethyl)pyrazine-2-carboxamide;-   N-(2-(1H-imidazol-2-yl)propyl)-3-amino-6-bromo-5-(trifluoromethyl)pyrazine-2-carboxamide;-   3-Amino-6-bromo-N-(2-morpholinoethyl)-5-(trifluoromethyl)pyrazine-2-carboxamide;    or-   3-Amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid    [2-(4-fluoro-phenyl)-2-oxo-ethyl]-amide.

Embodiment 43

The compound according to embodiment 39, wherein the compound is

-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    (3,3,3-trifluoro-2-hydroxy-propyl)-amide;-   3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid    ((S)-3,3,3-trifluoro-2-hydroxy-propyl)-amide;-   3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid    ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;-   3-Amino-5,6-bis-trifluoromethyl-pyridine-2-carboxylic acid    ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;-   3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid    ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;-   3-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic    acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;-   3-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic    acid ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;-   3-amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic    acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide;-   3-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic    acid (2-hydroxy-2-methyl-propyl)-amide; or-   3-Amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid    ((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide.

Embodiment 44

Use of a compound according to embodiment 1 to 43 in the manufacture ofa medicament for use in the treatment of an inflammatory or obstructiveairways disease or mucosal hydration.

Embodiment 45

Use of a compound according to embodiment 1 to 43 in the manufacture ofa medicament for use in the treatment of a disease mediated by CFTR.

Embodiment 46

Use of a compound according to embodiment 42 in the manufacture of amedicament for use in the treatment of a disease mediated by CFTR,wherein the disease is CF or COPD.

Embodiment 47

Use of a compound according to embodiment 1 to 43 in the manufacture ofa medicament for use in the treatment of cystic fibrosis.

Embodiment 48

A pharmaceutical composition for treating a disease or disorder mediatedby CFTR, comprising:

-   -   the compound according to embodiment 1 to 43 and    -   one or more pharmaceutically acceptable excipients.

Embodiment 49

A pharmaceutical composition, according to embodiment 48, wherein thedisease or disorder is cystic fibrosis or COPD.

Embodiment 49

A pharmaceutical composition, according to embodiment 49, wherein thedisease or disorder is cystic fibrosis.

Embodiment 50

A pharmaceutical combination, comprising:

-   -   a first active comprising the compound according to embodiment 1        to 43 and    -   a second active selected from osmotic agents, ENaC blockers,        anti-inflammatory agents, bronchodilatory agents, antihistamine        agents, anti-tussive agents, antibiotic agents and DNase drug        substances, wherein the first and second actives may be in the        same or different pharmaceutical composition.

Embodiment 51

A pharmaceutical combination according to embodiment 50, wherein thesecond active agent is an EnaC blocker.

Embodiment 52

A process for the preparation of compounds of formula (I), comprising:

-   -   reacting a compound 1 with compound 2 in a peptide coupling        reaction,

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as defined herein and P is asuitable amino protecting group;

-   -   removing protecting groups and isolating the compound of formula        I.

Embodiment 53

The process according to embodiment 48, wherein the peptide couplingcondition is HATU in an aprotic solvent.

We claim:
 1. A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein: A is N orCR^(4a); R¹ is H; C₁-C₈ alkyl optionally substituted by one or morehalogen atoms; C₂-C₈ alkenyl; C₂-C₈ alkynyl; C₃-C₁₀ cycloalkyl; C₅-C₁₀cycloalkenyl; —C₁-C₄ alkyl-C₃-C₈ cycloalkyl; C₁-C₈ alkoxy optionallysubstituted by one or more halogen atoms; halogen; SO₂NR⁸R⁹; SO₂R¹⁰;S—C₁-C₈alkyl optionally substituted by one or more halogen atoms;S—C₆-C₁₄ aryl; CN; NR¹¹R¹²; C(O)NR¹³R¹⁴; NR¹³SO₂R¹⁵; NR¹³C(O)R¹⁵,CO₂R¹⁵, —(C₀-C₄ alkyl)-C₆-C₁₄ aryl; or —(C₀-C₄ alkyl)-3 to 14 memberedheterocyclic group, wherein the heterocyclic group contains at least oneheteroatom selected from N, O and S; wherein the cycloalkyl,cycloalkenyl, aryl and heterocyclyl groups are each optionallysubstituted by one or more Z substituents; R² is C₁-C₄ haloalkyl; R³ andR^(4a) are each independently H or C₁-C₈ alkyl optionally substituted byone or more halogen atoms; R⁴ is H, or C₁-C₈ alkyl optional substitutedwith one or more halogen; R⁵ is —(CH₂)_(m)—NR¹⁷R¹⁸, —(CH₂)_(m)—OR′,C₁-C₈ alkoxy optionally substituted by one or more halogen atoms;—(C₀-C₄ alkyl)-CO₂R¹⁵; —(C₀-C₄ alkyl)-C₆-C₁₄ aryl or -3 to 14 memberedheterocyclic group, wherein the heterocyclic group contains at least oneheteroatom selected from N, O and S; wherein the —(C₀-C₄ alkyl)-C₆-C₁₄aryl and —(C₀-C₄ alkyl)-3 to 14 membered heterocyclic group are eachoptionally substituted by one or more Z substituents; R⁶ is C₁-C₈ alkyloptionally substituted by one or more halogen atoms; C₃-C₁₀ cycloalkyl;—C₁-C₄ alkyl-C₃-C₈ cycloalkyl; C₁-C₈ alkoxy optionally substituted byone or more halogen atoms; OH; CN; halogen; —(C₀-C₄ alkyl)-C₆-C₁₄ aryl;or —(C₀-C₄ alkyl)-3 to 14 membered heterocyclic group, wherein theheterocyclic group contains at least one heteroatom selected from N, Oand S; wherein the cycloalkyl, cycloalkenyl, —(C₀-C₄ alkyl)-C₆-C₁₄ aryland —(C₀-C₄ alkyl)-3 to 14 membered heterocyclic group are eachoptionally substituted by one or more Z substituents; or R⁶ is H, and R⁵is —(CH₂)_(m)—NR¹⁷R¹⁸, —(CH₂)_(m)—OR′, C₁-C₈ alkoxy optionallysubstituted by one or more halogen atoms; —(C₀-C₄ alkyl)-C₆-C₁₄ aryl;—(C₀-C₄ alkyl)-3 to 14 membered heterocyclic group, wherein theheterocyclic group contains at least one heteroatom selected from N, Oand S; or —(C₀-C₄ alkyl)-CO₂R¹⁵, wherein —(C₀-C₄ alkyl)-C₆-C₁₄ aryl and—(C₀-C₄ alkyl)-3 to 14 membered heterocyclic group groups are eachoptionally substituted by one or more Z substituents; or R⁴ and R⁶together with the carbon atoms to which they are bound form a 3 to 8membered carbocyclic ring system; or R⁴ and R⁵ together form an oxogroup (C═O) and R⁶ is C₁-C₄ alkyl optionally substituted by one or morehalogen atoms; C₁-C₄ alkoxy optionally substituted by one or morehalogen atoms; —(C₀-C₄ alkyl)-C₆-C₁₄ aryl; or —(C₀-C₄ alkyl)-3 to 14membered heterocyclic group, wherein the heterocyclic group contains atleast one heteroatom selected from N, O and S, wherein the aryl andheterocyclyl groups are each optionally substituted by one or more Zsubstituents; or R⁵ and R⁶ together with the carbon atoms to which theyare bound a 5 to 8 membered heterocyclic ring system containing one ormore heteroatoms selected from N, O and S, wherein the ring system isoptionally substituted by one or more Z substituents; or R⁴ and R⁵ andR⁶ together with the carbon atoms to which they are bound form a 5 to 8membered heterocyclic ring system containing one or more heteroatomsselected from N, O and S, wherein the ring system is optionallysubstituted by one or more Z substituents; R′ is H, or C₁-C₈ alkyloptional substituted with one or more halogen; m is 0, 1, 2 or 3; R⁸,R¹¹, R¹³ and R¹⁷ are each independently H, C₁-C₈ alkyl optionallysubstituted by one or more halogen atoms, C₃-C₁₀ cycloalkyl or —(C₁-C₄alkyl)-C₃-C₈ cycloalkyl; R⁹, R¹⁰, R¹², R¹⁴, R¹⁵, R¹⁶ and R¹⁸ are eachindependently H; C₁-C₈ alkyl optionally substituted by one or morehalogen atoms; C₂-C₈ alkenyl; C₂-C₈ alkynyl; C₃-C₁₀ cycloalkyl; C₅-C₁₀cycloalkenyl; —C₁-C₄ alkyl-C₃-C₈ cycloalkyl; —(C₀-C₄ alkyl)-C₆-C₁₄ aryl;or —(C₀-C₄ alkyl)-3 to 14 membered heterocyclic group, wherein theheterocyclic group contains at least one heteroatom selected from N, Oand S, wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclylgroups are each optionally substituted by one or more Z substituents; orR⁸ and R⁹, R¹¹ and R¹², R¹³ and R¹⁴, and R¹⁷ and R¹⁸ together with thenitrogen atom to which they are attached may form a 4 to 14 memberedheterocyclic group optionally substituted by one or more Z substituents;Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C₁-C₆ alkyloptionally substituted by one or more OH groups or NH₂ groups, C₁-C₆alkyl optionally substituted by one or more halogen atoms, C₁-C₆ alkoxyoptionally substituted by one or more OH groups or C₁-C₄ alkoxy,(SO₂)NR¹⁹R²¹, (SO₂)R²¹, C(O)NR¹⁹R²¹, NR¹⁹R²¹, C(O)OR¹⁹, C(O)R¹⁹, SR¹⁹,OR¹⁹, oxo, CN, NO₂, halogen or a 3 to 14 membered heterocyclic group,wherein the heterocyclic group contains at least one heteroatom selectedfrom N, O and S; R¹⁹ and R²¹ are each independently H; C₁-C₈ alkyl;C₃-C₈ cycloalkyl; C₁-C₄ alkoxy-C₁-C₄ alkyl; (C₀-C₄ alkyl)-aryloptionally substituted by one or more groups selected from C₁-C₆ alkyl,C₁-C₆ alkoxy and halogen; (C₀-C₄ alkyl)-3- to 14-membered heterocyclicgroup, the heterocyclic group including one or more heteroatoms selectedfrom N, O and S, optionally substituted by one or more groups selectedfrom halogen, oxo, C₁-C₆ alkyl and C(O)C₁-C₆ alkyl; (C₀-C₄ alkyl)-O-aryloptionally substituted by one or more groups selected from C₁-C₆ alkyl,C₁-C₆ alkoxy and halogen; and (C₀-C₄ alkyl)-O-3- to 14-memberedheterocyclic group, the heterocyclic group including one or moreheteroatoms selected from N, O and S, optionally substituted by one ormore groups selected from halogen, C₁-C₆ alkyl or C(O)C₁-C₆ alkyl;wherein the alkyl groups are optionally substituted by one or morehalogen atoms, C₁-C₄alkoxy, C(O)NH₂, C(O)NHC₁-C₆ alkyl or C(O)N(C₁-C₆alkyl)₂; or R¹⁹ and R²¹ together with the nitrogen atom to which theyattached form a 5- to 10-membered heterocyclic group, the heterocyclicgroup including one or more further heteroatoms selected from N, O andS, the heterocyclic group being optionally substituted by one or moresubstituents selected from OH; halogen; aryl; 5- to 10-memberedheterocyclic group including one or more heteroatoms selected from N, Oand S; S(O)₂-aryl; S(O)₂—C₁-C₆ alkyl; C₁-C₆ alkyl optionally substitutedby one or more halogen atoms; C₁-C₆ alkoxy optionally substituted by oneor more OH groups or C₁-C₄ alkoxy; and C(O)OC₁-C₆ alkyl, wherein thearyl and heterocyclic substituent groups are themselves optionallysubstituted by C₁-C₆ alkyl, C₁-C₆ haloalkyl or C₁-C₆ alkoxy.
 2. Thecompound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein A is CR^(4a).
 3. The compound according to claim 1, ora pharmaceutically acceptable salt thereof, wherein R¹ is C₁-C₈ alkyloptionally substituted by one or more halogen atoms; C₁-C₈ alkoxyoptionally substituted by one or more halogen atoms; halogen; NR¹¹R¹²,C₆-C₁₄ aryl; or —(C₀-C₄ alkyl)-5 to 6 membered heterocyclic group,wherein the heterocyclic group contains at least one heteroatom selectedfrom N, O and S, wherein the aryl and heterocyclic groups are eachoptionally substituted by one or more Z substituents.
 4. The compoundaccording to claim 3, or a pharmaceutically acceptable salt thereof,wherein R¹ is C₁-C₄ alkyl optionally substituted by one or more halogenatoms; C₁-C₄ alkoxy optionally substituted by one or more halogen atoms;or halogen.
 5. The compound according to claim 3, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is aryl, wherein aryl is phenyloptionally substituted by one or more Z substituents.
 6. The compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof,wherein R² is CF₃.
 7. The compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein R⁴ is H or C₁-C₄ alkyloptionally substituted by one or more halogen atoms; R⁵ is C₁-C₄ alkoxyoptionally substituted by one or more halogen atoms; —(CH₂)_(m)—NR¹⁷R¹⁸,—(CH₂)_(m)—OR; or —(C₀-C₄ alkyl)-3 to 14 membered heterocyclic group,wherein the heterocyclic group contains at least one heteroatom selectedfrom N, O and S, wherein the aryl heterocyclyl groups is optionallysubstituted by one or more Z substituents; R⁶ is C₁-C₄ alkyl optionallysubstituted by one or more halogen atoms; C₁-C₄ alkoxy optionallysubstituted by one or more halogen atoms; or —(C₀-C₄ alkyl)-C₆-C₁₄ arylwherein the aryl is optionally substituted by one or more Zsubstituents; or R⁴ and R⁶ together with the carbon atoms to which theyare bound form a 3 to 6 membered carbocyclic ring system; or R⁵ and R⁶together with the carbon atoms to which they are bound form a 5 to 8membered heterocyclic ring system containing one or more heteroatomsselected from N, O and S, wherein the ring system is optionallysubstituted by one or more Z substituents; m is 0 or 1; R¹⁷ and R¹⁸ areeach independently H; C₁-C₈ alkyl optionally substituted by one or morehalogen atoms.
 8. The compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein A is CR^(4a); R¹ isC₁-C₄ alkyl optionally substituted by one or more halogen atoms; orC₁-C₄ alkoxy optionally substituted by one or more halogen atoms; R² isCF₃, R³ is H, CH₃ or CF₃; R⁴ is H or Me; R^(4a) is H; R⁵ is —NR¹⁷R¹⁸ orOH, and R⁶ is C₁-C₄ alkyl optionally substituted by one or more halogenatoms.
 9. The compound represented by formula II,

or a pharmaceutically acceptable salt; wherein A is N or CR^(4a); R^(a)is H or C₁-C₄ alkyl; R¹ is C₁-C₈ alkyl optionally substituted by one ormore halogen atoms; C₁-C₈ alkoxy optionally substituted by one or morehalogen atoms; halogen; NR¹¹R¹², C₆-C₁₄ aryl; or —(C₀-C₄ alkyl)-5 to 6membered heterocyclic group, wherein the heterocyclic group contains atleast one heteroatom selected from N, O and S, wherein the aryl andheterocyclic groups are each optionally substituted by one or more Zsubstituents; R₃ is H or CH₃; R¹⁰¹ is


10. A pharmaceutical composition, comprising: the compound according toclaim 1, or a pharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable excipients.
 11. A pharmaceuticalcombination, comprising: a first active comprising the compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof, anda second active selected from osmotic agents, ENaC blockers,anti-inflammatory agents, bronchodilatory agents, antihistamine agents,anti-tussive agents, antibiotic agents and DNase drug substances,wherein the first and second actives may be in the same or differentpharmaceutical composition.
 12. A method the symptomatic treatment ofcystic fibrosis, asthma, or COPD, comprising: administering an effectiveamount of at least one compound according to claim 1, or apharmaceutically acceptable salt thereof, to a subject in need of suchtreatment.